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Hypercortisolemia Corticotroph Adenomas and Cushings Disease

The first step in diagnosing a patient with hypercortisolemia (Cushing's syndrome) is to find the etiology. In the subset of causes of Cushing's syndrome in the pediatric population, 85 of cases resulted from Cushing's disease.8 Patients diagnosed with Cushing's disease, thus having ACTH-releasing corti-cotroph adenomas, exhibit cushingoid features. Most often, these features in children are short stature, rapid weight gain, menstrual irregularities, skin striae, and mental status changes.9 To demonstrate that hypersecretion of cortisol is present, tests such as the 24-hour urinary free cortisol, 17-hydroxycorticosteroid, and creatinine excretion tests are performed.8 The normal diurnal variation in secretion of cortisol is also lost in Cushing's disease. The high- and low-dose dexamethasone suppression tests are also administered, with the dose of dexamethasone given according to body weight, and these tests have important diagnostic implications. These dynamic tests measure cortisol...

Hypercortisolism cushings syndrome epidemiology and etiology

Cushing's syndrome refers to the pathophysiologic changes associated with exposure to supraphysiologic cortisol concentrations (endogenous hypercortisolism) or pharma-cologic doses of glucocorticoids (exogenous hypercortisolism). Cushing's syndrome from endogenous causes is a rare condition, with an estimated incidence of two to five cases per 1 million persons per year.14 Patients receiving chronic supraphysiologic doses of glucocorticoids, such as those with rheumatologic disorders, are at high risk of developing Cushing's syndrome.

Cardiovascular Risk Factors

As waist circumference increases, visceral adiposity increases. Visceral adipose tissue is metabolically highly active. An important conceptual shift has occurred in recent years with respect to how adipose tissue is viewed. It is no longer seen as a passive storage site for excess caloric ingestion. Instead, it is clear that visceral adipose tissue displays many features of an endocrine organ (Bradley et al., 2001 Toth, 2005a) (Fig. 27-3). Visceral adipose tissue produces a variety of inflammatory cytokines (tumor necrosis factor, transforming growth factor-p), interleukins (IL-1, IL-6), and effector molecules that regulate appetite (leptin) as well as insulin sensitivity and resistance (e.g., adiponectin, resistin). As the mass of visceral adipose tissue increases, adiponectin production decreases, which is associated with increased insulin resistance in adipose tissue, skeletal muscle, and the hepatic parenchyma (see Fig. 27-3). As adipose tissue becomes more insulin resistant, the...

Treatment of Special Populations

Glucocorticoids play a significant role in bone remodeling. Exogenous glucocorticoid administration results in an increase in bone resorption, inhibition of bone formation, and change in bone quality. Glucocorticoids (e.g., prednisone, hydrocortisone, methyl-prednisolone, and dexamethasone) promote bone resorption through reduced calcium absorption from the GI tract and increased renal calcium excretion. Bone formation is reduced through inhibition of osteoblasts. They also decrease estrogen and testosterone production.

Abnormal HPG Regulation

Although several mechanisms that parallel obesity to infertility have been proposed, many remain ambiguous and relatively undefined. Studies indicate that the central factor linking the mechanisms associated with obesity and infertility is an abnormal regulation of the HPG axis, as well as the previously discussed OS. The HPG axis responds to fluctuations in hormones causing a range of widespread and local effects on the body and aspects of reproduction. Excess fat accumulation can impair the feedback regulation of the HPG axis and be a contributing factor to abnormal semen quality. Since sex steroids and glucocorticoids control the interaction between the hypothalamic-pituitary-adrenal (HPA) and the HPG axes, any imbalance may in turn affect spermatogenesis and male reproductive function. The abnormal endocrine changes observed in obese, infertile men are not similar to men with either obesity or infertility alone. Therefore, simultaneous irregular hormonal profile and...

Acute Adrenal Insufficiency Related to Bilateral Adrenal Hemorrhage

Veins Fragile Adrenal

Stress may lead to bilateral adrenal hemorrhage or may cause acute adrenal insufficiency without hemorrhage. The burn patient is an example of this dual situation apparently related to a similar stress. Among 807 patients treated at Parkland Hospital over the previous 6 years, Murphy and colleague28 found 3 patients in whom acute adrenal insufficiency developed. They reviewed the existing theories of the pathophysiology of adrenal insufficiency in the burn patient. Vaughan and associates demonstrated Cortisol levels three to four times higher than normal in patients with burns greater than 30 . These patients lost their diurnal rhythm. Burn size correlated with Cortisol but not corticotropin levels.29 Hemorrhagic cortical necrosis is the most common pathologic finding associated with this acute adrenal insufficiency.28 The clinical picture is that of sudden and rapid cardiovascular collapse, which is frequently interpreted as sepsis. When the diagnosis of adrenal insufficiency is...

Neuropeptides In Psychiatric Disorders

Among the better explored connections is the role of CRH in stress-related disorders, including depression (Holsboer, 2001a,b Harro and Oreland, 2001 De Souza and Grigoriadis, 2002). Levels of CRH in the CSF have been found to be higher and CRH receptor densities lower in some populations of depressed patients, and the number of CRH-expressing neurons in the hypothalamic paraventricular nucleus is higher. Recurrence of depression can be fairly well predicted on the basis of enhanced cortisol response to CRH after dexamethasone-induced feedback inhibition of anterior pituitary (Reul and Holsboer, 2002). Several nonpeptide antagonists of the CRH1 receptor subtype have recently been developed. There is preliminary evidence that such drugs may be efficient against anxiety and depression (Zobel et al., 2000).

Mecanism Of Centripetal Lipid Accumulation Supraclavicular Fat And Face

Corticotroph cells produce ACTH and constitute 10 to 20 of the anterior lobe. Corticotrophs are concentrated in the central third of the gland but are also found in the lateral wings of the adenohypophysis and in the pars intermedia. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis. Corticotropin-releasing hormone (CRH) made by the par-aventricular neurons in the hypothalamus stimulate the release of ACTH. ACTH is synthesized as part of the precursor proopiomelanocortin (POMC), which is cleaved into pro-ACTH and b-lipotropin (PLPH). Further processing of pro-ACTH yields ACTH, corticotrophin-like intermediate lobe peptide (CLIP), endorphin, lipotropin, and melanocyte-stimulating hormone (MSH). The major role of ACTH is to stimulate steroidogenesis in the adrenal cortex, which results in the syn thesis and release of cortisol. Cortisol exerts negative feedback at the pituitary and the hypothalamus. Regulation of cortisol by the brain is through CRH release and...

Androgen dynamics in women

The three sources from which androgens in women arise from are the adrenal cortex, the ovarian theca (and to a lesser degree, ovarian stromal cells), and by peripheral bioconversion of circulating androgenic prohormones. The adrenal gland produces about 95 of circulating serum dehydroepiandrosterone (DHEAS, the production rate of which is 19 mg day in young women) and 50 of dehydroepiandrosterone (DHEA, the production rate of which is 16 mg day). The rest of circulating DHEA is produced by peripheral conversion of DHEAS (30 ) in addition to a small ovarian contribution (20 ) (Burger 2002). DHEAS circulates unbound to protein, has virtually no androgenic action, and has a half-life of 10 hours it serves as a circulating prohormone for production of DHEA and the more potent downstream androgens both in the circulation and in peripheral tissues. Twenty-eight percent of DHEA comes from hydrolysis of DHEAS, and about 31 of DHEA is sulfated to DHEAS (Haning etal. 1989 Bird etal. 1978). The...

Regulation Of Srebp Isoform Expression

Plasma Fplc

Taken together, the above evidence suggests that SREBP-lc mediates insulin's lipogenic actions in liver. This observation led to the discovery that SREBP-lc contributes to the development of hepatic steatosis or fatty liver associated with diabetes, obesity, and the metabolic syndrome. Hepatic steatosis is the most commonly encountered liver abnormality in the United States, owing to its strong association with obesity and insulin-resistant diabetes mellitus (Mokdad et al. 200l). Conservative estimates indicate that 40-60 of individuals with obesity or diabetes develop fatty livers. A subset of patients with fatty liver will subsequently develop fibrosis, cirrhosis, and liver failure. Data initially obtained in mice indicate that the fatty liver associated with insulin resistance is caused, in part, by increased SREBP-lc expression. The increased SREBP-lc expression occurs in response to the high insulin levels present in insulin-resistant states. Thus, SREBP-lc levels are elevated in...

Results Clinical data

Of 28 patients diagnosed between 1951 and 1959, 16 died of cortisol insufficiency precipitated by concurrent illnesses. In contrast, only two patients died in the group diagnosed between 1960 and 1970. This marked decrease in mortality was secondary to a better and regular follow-up and an improvement in their education regarding the nature and life-endangering risks of the disease. The salient clinical features are summarized in Table 3. Gonadal insufficiency was present in 94 of the patients, cortisol insufficiency in 96 and thyroid insufficiency in 88 . The earliest sign of pituitary failure was the inability to lactate. Three patients had scanty menses for Cortisol insufficiency Cortisol reserve was studied in all patients before replacement therapy. The basal urinary hydroxycorticosteroids ranged from undetect-able values to 1.0 mg day in the patients who did not show pituitary reserve. The response to ACTH, 40 units twice a day for 4 days (ACTHAR gel) was arbitrarily classified...

Temperament and Personality

One of the earliest indicators of vulnerability to the development of anxiety is behavioral inhibition, characterized by increased physiological reactivity or behavioral withdrawal in the face of novel stimuli or challenging situations (Kagan and Reznick, 1986). Behavioral inhibition may be a manifestation of a biological predisposition characterized by both overt behavioral (e.g. cessation of play, reluctance to interact in the presence of unfamiliar objects and people) and physiologic indicators (e.g. low heart rate variability, accelerated heart rate, increased salivary cortisol level, pupillary dilation, increased cortisol level). There is an increased frequency of behavioral inhibition among children of parents with anxiety disorders compared to those of normal controls (Biederman et al., 1991 1993 Beidel and Turner., 1997 Turner et al., 1987 Rosenbaum et al., 1991 1993 1988 Sylvester et al., 1988). The link between childhood allergies, eczema and...

Addisons Disease and Acute Adrenal Hemorrhage

The adrenal gland produces glucocorticoids and miner-alocorticoids. Glucocorticoid production is regulated by the hypothalamic-pituitary-adrenal axis. In response to a variety of stimuli from within the brain, corticotropin-releasing factor (CRF) is released into the portal circulation of the pituitary, which in turn stimulates the secretion of adreno-corticotropin (corticotropin). Corticotropin then enters the systemic circulation, where it stimulates the production and secretion of glucocorticoids and, to a lesser extent, miner-alocorticoids. In the adrenal cortex, corticotropin stimulates the conversion of cholesterol to corticosteroids. Adequate circulating levels of corticosteroids returning to the brain inhibit the production of CRF and corticotropin. Cortisol, corticotropin, and CRF are secreted with a diurnal variation, with levels higher in the morning than in the afternoon. Plasma Cortisol levels are highest at 8 am and lowest between 10 pm and 2 am. Stress disrupts the...

Preoperative Evaluation and Preparation

To determine whether an incidental adrenal mass in an asymptomatic patient is functional is obligatory, because virtually all functioning tumors should be excised and preoperative preparation is crucial for minimizing perioperative complications. In these instances, the evaluation should include a thorough history and physical examination and biochemical screening for occult aldosteronomas, pheochromocytomas, and gluco-corticoid-producing adenomas. Serum potassium, sodium, free testosterone, dehydroepiandrosterone (DHEA), and estradiol are measured. Plasma Cortisol and corticotropin measurement in the morning and in the afternoon, or urine cortisone for 24 hours, are performed to rule out Cushing's syndrome. If there is any suspicion that the Cortisol level is abnormal, then measurements are repeated after administration of 1 mg of dexamethasone (occasionally after 8 mg), and a blood sample is obtained at 8 am the following morning for plasma Cortisol. A 24-hour urine sample is...

Effects of exogenous testosterone on cardiovascular risk factors

Morbidly obese and insulin resistant men frequently have low serum levels of testosterone which increase upon weight loss (Leenen et al. 1994). Estradiol levels show the opposite changes to testosterone with obesity and weight loss. It has therefore been suggested that obesity causes hypotestosteronemia by increased aro-matisation of testosterone to estradiol in the adipose tissue. Supporting a role of insulin in the determination of testosterone levels in men, infusion of insulin during euglycemic clamp increased testosterone levels in obese men but not in lean men (Pasquali et al. 1997). On the other hand, hypogonadal men are frequently obese with increased levels of leptin and insulin (Couillard etal. 2000). Body weight, leptin levels and insulin levels decrease upon substitution of testosterone in hypogonadal men (Behre etal. 1997). Even treatment of eugonadal obese men with testosterone led to a decrease of visceral fat mass and, in parallel, improved insulin sensitivity and...

Hormonal Response in Posttraumatic Stress Disorder

In a well-functioning person, stress produces rapid and pronounced hormonal responses. However, chronic and persistent stress inhibits the effectiveness of the stress response and induces desensitization. PTSD develops following exposure to events that overwhelm the individual's capacity to reestablish homeostasis. Instead of returning to baseline, there is a progressive kindling of the individual's stress response. Initially only intense stress is accompanied by the release of endogenous, stress-responsive neurohormones, such as cortisol, epinephrine, norepinephrine (NE), vasopressin, oxytocin, and endogenous opioids. In PTSD even minor reminders of the trauma may precipitate a full-blown neuroendocrine stress reaction It permanently alters how an organism deals with its environment on a day-to-day basis, and it interferes with how it copes with subsequent acute stress. A review of the neuroendocrine findings in PTSD to date shows very specific abnormalities in this disorder,...

Interpretation of results

We exploited the fact that nandrolone and 7a-methyl nandrolone (MENT) have 3- and 10-fold increased androgen receptor binding affinity as compared to testosterone, respectively (Bergink etal. 1985 Kumar etal. 1999). However, these andro-gens have not been developed further for oral application due to their limited oral efficacy. The oral efficacy of MENT was expected since both high androgen receptor activity and high metabolic stability have been reported using rat liver microsomes (Agarwal and Monder 1988). Our metabolic stability assay, using intact human hep-atocytes, indicates that there is no difference in the metabolism between nandrolone, MENT and the metabolically unstable reference androgen, testosterone. A plausible explanation for this difference is that the cofactor (NAD) for the most important androgen inactivating enzyme, the microsomal enzyme 17 -hydroxysteroid dehydrogenase type 2, is not added to the microsomal preparation (Puranen etal. 1999). In addition, the low...

What Complications Can Occur With Convulsive Status Epilepticus

Stasis, possible thrombosis Increased prolactin and Cortisol Status epilepticus prompts Cortisol and prolactin release, although prolactin may become exhausted and return to normal levels in prolonged SE. Leukocytosis and spinal fluid pleocytosis may occur,9,13 but these problems should not be attributed to the SE itself until infection or some other cause of inflammation has been excluded. Aspiration pneumonia is common if airway protection is not assured. Respiratory failure is probably more often due to medications than to SE itself.

Factors affecting serum testosterone levels in elderly men

In clinical studies, body mass index (BMI) emerges as an important determinant of SHBG levels (Demoor and Goossens 1970). For the whole range of BMI values encountered clinically there is a highly significant negative correlation with SHBG and testosterone serum levels, explained at least in part by increased insulin levels (Giagulli etal. 1994 Khaw and Barrett-Connor 1992 Plymate etal. 1988). In elderly men this inverse relationship between BMI and SHBG levels can be clearly demonstrated notwithstanding the background of an age-related rise of SHBG levels (Vermeulen et al. 1996). Similarly, a negative association of serum SHBG and total testosterone with leptin levels has been observed in elderly men (Haffner et al. 1997 Van den Saffele et al. 1999). Negative associations with serum testosterone levels tend to be most pronounced for indices of abdominal fat (Couillard et al. 2000 Haffner et al. 1993 Khaw and Barrett-Connor 1992 Vermeulen et al. 1999a). Whereas moderate obesity...

Cytokines Influence on Steroidogenesis

Testicular Steroidogenesis

Fig. 9.2 Influence of inflammatory mediators on Leydig cell and testosterone synthesis. Inflammatory mediators, like ROS, lipopolysaccharides (LPSs), NO, or cytokines, inhibit testosterone production in Leydig cells because of their activity against steroidogenic acute regulatory (StAR) protein, 3 -hydrosteroid dehydrogenase (3b-HSD), P450c17, or 17 -hydroxysteroid dehydrogenase Fig. 9.2 Influence of inflammatory mediators on Leydig cell and testosterone synthesis. Inflammatory mediators, like ROS, lipopolysaccharides (LPSs), NO, or cytokines, inhibit testosterone production in Leydig cells because of their activity against steroidogenic acute regulatory (StAR) protein, 3 -hydrosteroid dehydrogenase (3b-HSD), P450c17, or 17 -hydroxysteroid dehydrogenase

Fun and Laughter Remember Us

The same medical researchers found that laughter stimulates the immune system. Humor and exercise trigger similar physiological processes. The study group that laughed a lot, known as the laughter group, showed increased levels of good hormones, such as endorphins and neurotransmitters, and decreased levels of stress hormones, including Cortisol and adrenaline. Laughter is our body's safety valve that

Multifocal Langerhans Cell Histiocytosis

When making the diagnosis of multifocal LCH, it is important to fully assess the extent of body involvement. The prognosis is thought to be substantially worse in the presence of soft-tissue involvement (e.g., lymph nodes, liver, spleen, skin) than if only multifocal bone lesions are present.12 A typical screening for extent of systemic involvement would include a detailed history and physical examination, complete blood count, coagulation and liver profiles, nuclear scintigraphy, and skeletal survey. Further, the Histiocyte Society recommends that all LCH patients at initial diagnosis undergo the following evaluations height, weight, pubertal status, water deprivation test for diabetes insipidus, baseline hormone studies (T4, thyroid-stimulating hormone, cortisol, follicle-stimulating hormone, luteinizing hormone, and prolactin), baseline age-appropriate tests of intellectual and motor development, and behavioral tests, as well as brain MRI with a contrast agent.

Depression In Theoretical Perspective

Were typical of research in this area. It found a concordance rate for depression of 46 percent in identical twins. In nonidentical twins, however, the concordance rate was only 20 percent.3 This seems to suggest that there is a heritability component with regard to the cause of depression. It has been proposed that this genetic proclivity translates into neurological irregularities, and some researchers point to low levels of serotonin as a possible precipitator of depression. Others have offered evidence that dysfunctional structures and processes within the neuroendocrine system, and in particular the hypothalamic-pituitary-adrenocortical axis, may lead to the experience of depression. For instance, an oversecretion of cortisol, an adrenocortical hormone, has been linked to the experience of depression.

Disorders of sleeping

Frieboes et al. (1999) noted a number of alterations to sleep-endocrine relationships months to years following TBI. These included reduction in non-REM stage 2 sleep in the first half of the night and increased REM sleep in the second sleep cycle. With regard to endocrine functioning the nocturnal growth hormone peak was blunted and the maximal prolactin secretion was increased but the cortisol levels were unchanged.

Physical Appearance

Limbs Noonan Syndrome

Infants with dome-shaped pulmonary valve stenosis occasionally have chubby, round, bloated faces with highly colored cheeks (Fig. 11-7A) and well-developed fat deposits.122 The digits may be erythematous or frankly red in response to a small or intermittent right-to-left shunt through a patent foramen ovale (see Chapter 16).

Pathomechanism and hormonal dysregulation in overtraining

Endogenous hormones are of major importance both in supplying energy during physical exercise and in the adaptations during the subsequent regeneration period. Depending on the duration and intensity of physical exercise, and during periods of intense training or repetitive competitions, changes in the blood concentrations of hormones can be measured, e.g. a decrease of the testosterone cortisol ratio, which indicate an alteration of the anabolic-catabolic balance and can be reversed by regenerative measures. Some authors even describe correlations to training-induced changes of strength 59 . However, it seems that the testosterone cortisol ratio reflects more the actual physiological strain of training than an OTS 48,58 . Cortisol concentrations in particular at rest may change in a biphasic way showing an increase during acute overload training and decreasing in chronic OTS. Hormonal changes also seem to play an essential role with regard to the pathomechanisms involved in OTS,...

Physiology anatomy and biochemistry of the adrenal gland

Adrenal Glands Anatomy

The zona fasciculata produces the glucocorticoid hormone cortisol. Cortisol is responsible for maintaining homeostasis of carbohydrate, protein, and fat metabolism. Its secretion follows a circadian rhythm, generally beginning to rise at approximately 4 am and peaking around 6 to 8 am. Thereafter, cortisol levels decrease throughout the day, approach 50 of the peak value by 4 pm, and reach their nadir around midnight. The normal rate of cortisol production is approximately 8 to 15 mg day. Cortisol plays a key role in the body's response to stress. Its production increases markedly during physiologic stress such as during acute illness, surgery, or trauma. In addition, certain conditions such as alcoholism, depression, anxiety disorder, obsessive-compulsive disorder, poorly controlled diabetes, morbid obesity, starvation, anorexia nervosa, and chronic renal failure are associated with increased cortisol levels. High total cortisol levels are also observed in the presence of increased...

Treatment with DHEA clinical studies

The classical approach to study the physiological role of a hormone in humans is to analyze the effect of a hormonal deficit and the changes induced by replacement of the missing hormone. Thus adrenal insufficiency is the most useful model disease to understand the clinical activity of DHEA. As in adrenal insufficiency (AI) not only DHEA but also cortisol and (in primary AI) aldosterone is lacking, one might speculate that replacement of cortisol and aldosterone alone is not sufficient to fully restore wellbeing in AI. Intriguingly, it has only recently been clearly demonstrated that replacement of glucocorticoids (GC) and mineralocorticoids (MC) alone is indeed not sufficient to fully compensate the impairment of health induced by AI. completed in England however, up to now the results have only been presented in abstract form (Gurnell et al. 2002). Three of the trials studied women only (Arlt et al. 1999a Johannsson et al. 2002 Lovas et al. 2003), whereas the other two trials...

Regulation of pregnenolone metabolism

The presence of many steroid-converting enzymes allows many different pathways to convert pregnenolone into testosterone (see Figure 1.1). Depending on whether pregnenolone is converted initially by the 3 -hydroxysteroid dehydrogenase A5-A4-isomerase complex or the P450C17 enzyme, a A4- or A5-pathway predominates. In the human testis most of the steroids are formed via the A5-pathway with dehydroepiandrosterone (DHEA) as the first C19 intermediate (Weusten et al. 1987b) (see Figure 1.3). The enzyme 3 -hydroxysteroid dehydrogenase A5-A4-isomerase (3SHSD) catalyses the conversion of A5-3 -hydroxysteroids to A4-3-ketosteroids, an essential step in the biosynthetic pathway. The dehydrogenase and isomerase activities are catalysed by one protein coded by one gene (Lachane etal. 1990). Although the two enzyme activities are carried out by one single protein, separate sites on the molecule mediate the specific enzyme activities (Luu-The etal. 1991). Different isoforms of this enzyme are...

Disturbances of neurovegetative functioning following TBI

These deep brain lesions are also thought to be related to the disruption of a variety of neurohormones including corticotrophin-releasing hormone (CRH), cortisol, vasopressin, and prolactin as well as disrupting other hormone systems including those related to the thyroid and the gonads as well as the hormones that control diuresis and glucose metabolism. For example, patients followed for 2 to 10 months following TBI demonstrated elevated morning levels of cortisol, absence of diurnal cortisol variation, and non-suppression to dexamethasone challenge (Cohen, Oksenberg, Snir, Stern, & Grosswasser, 1992). Glucose loading in acute TBI patients was associated with increase in growth hormone (King, Knowles, McLaurin et al., 1981), prolactin secretion was noted to be elevated at various stages following severe TBI (Valenta & De Feo, 1980) and it is postulated that this latter disturbance may be attributable to the hypothalamic mechanism that controls the hormone's secretion...

Table 461 Overview Of The Neuroendocrine Stress Response

After surgical insult includes a general increase in catabolic hormones, such as catecholamines, Cortisol, renin, aldosterone, and glucagon, which result in hyperglycemia, muscle protein catabolism (negative nitrogen balance), and increased lipolysis. In addition, there is sodium and water retention, with a shift of extracellular fluid to intracellular compartments.1 A general decrease in immune function and activation of coagulation are also associated with the stress response. The net result is a hypermetabolic, catabolic state resembling semistarvation.

Dexamethasone suppression test

A high- or low-dose dexamethasone test is used to aid diagnosis of Cushing's disease. A blood sample is taken and cortisol levels are measured. Intravenous dexamethasone is administered and blood cortisol levels are measured at 3 and 8 h following injection. In the normal animal, dexametha-sone suppresses adrenal function and an absence of cortisol is found in blood following administration of dexamethasone. In the animal with suspected Cushing's disease, a low-dose dexamethasone test will show incomplete suppression of cortisol production. A high-dose dexamethasone suppression test is used to distinguish between adrenal- and pituitary-dependent Cushing's disease.

Have been reported with PD pathophysiology

Amygdala Pathophysiology

Direct and indirect connections to the reticular activating system (RAS), a region spanning the medulla, pons, and midbrain, help to regulate arousal, vigilance, and fear. These connections are modulated by serotonin and norepinephrine, which have their primary origins in the RAS.14 The amygdala sends projections to the hypothalamus, thus influencing the autonomic nervous system to affect heart rate, blood pressure, and stress-associated changes. It also influences the hypothalam-ic-pituitary-adrenal (HPA) axis, leading to a cascade of stress hormones.15 One such hormone is cortisol, which, if elevated for prolonged periods, can damage the brain and other organs. These are important targets in our understanding of how the amygdala regulates the fear response.

Secondary Adrenal Insufficiency Related to Exogenous Steroid Usage

Adrenal suppression has been identified in patients using high-dose steroids for very short periods of time, and the longer the steroid use, the longer the impairment may last. No study has definitively answered how short an exposure to how much steroid is the minimum amount to suppress adrenal function. Graber and colleagues studied 14 patients 8 after resection of a functioning cortical adenoma and 6 after supraphysiologic doses of steroids for 1 to 10 years. During the first month without therapy, corticotropin failed to increase in these patients, despite low Cortisol levels. During the second to fifth months, plasma corticotropin rose to normal or supernormal values but the plasma corticosteroid response to corticotropin remained subnormal. During the sixth to ninth months, the plasma and urinary corticoid levels were normal, but adrenal responsiveness could be demonstrated only with supernormal levels of corticotropin. After 9 months, pituitary-adrenal responses returned to...

Evaluation Guidelines Table82

When visual loss due to a sellar process is suspected, pituitary and hypothalamic function should be evaluated. The basic outpatient endocrinological panel should include serum prolactin, growth hormone (GH) (after a 75-g oral glucose load), insulin-like growth factor-I, adrenocorticotropic hormone (ACTH), cortisol (serum morning sample or 24-hour urine free cortisol), thyroid-stimulating hormone (TSH), T3, T4, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone level. Low values, and even normal ones in some instances, are consistent with hypopituitarism. High values imply pituitary hypersecretion by a pituitary adenoma.

Localization Studies

Although the CT-based diagnosis of adenoma is reliable with acceptable certainty, it is worth noting that the CT-based diagnosis of hyperplasia is unreliable.52 The presence of non-aldosterone-secreting nodules in the ipsilateral or contralateral adrenal gland associated with an adenoma may result in a misdiagnosis as hyperplasia. In addition, hyperplasia may be associated with a unilateral macronodule and cause an erroneous diagnosis of an adenoma. Therefore, all patients with unilateral adenomas as small as 1 cm or bilateral nodules on CT and those with bilateral normal glands require further localization studies using isotope adrenal scanning or selective adrenal venous sampling for aldosterone and Cortisol levels, or both. Adrenal venous catheterization with blood sampling to measure aldosterone and Cortisol concentrations is still the most accurate test for the differential diagnosis of primary hyperaldosteronism.52-5660 Some investigators claim that adrenal venous sampling is a...

Vascular Maturation Regulates Adipose Tissue Plasticity

Adipose tissue endothelial cell proliferation and apoptosis in ob ob mice. Vasculature remodeling accompanies adipose tissue growth or regression. (A) Endothelial cell proliferation and apoptosis were evaluated in epididymal adipose tissue sections from ob ob mice following 7 days of TNP-470 or leptin treatment. Endothelial cells (red) were identified using vWF. BrdU was used to identify proliferating cells (green left images) and the TUNEL assay was used to identify apoptotic cells (green right images). Double-stained cells are yellow. Adipose tissue from control ob ob mice contained numerous proliferating endothelial cells (yellow, top left), occasional proliferating nonendothelial cells (green), and few apoptotic endothelial cells (yellow, top right). In contrast, adipose tissue from TNP-470-and leptin-treated mice contained abundant apoptotic endothe-lial cells (yellow, middle and bottom right). Bar, 25 pm. (B) Median percentages of endothelial cell...

The Bodys Response to Stress

Hypothalamus, and pituitary gland are activated. The amygdala and hypothalamus are parts of the brain associated with fear, stress, and the integration of bodily functions. The pituitary gland, which is controlled by the hypothalamus, is located just beneath the brain and releases hormones needed by the body. As part of the stress response, ACTH, a hormone released from the pituitary gland activates the adrenal glands, which in turn release the stress hormones, epineph-rine and cortisol (see Figure 9-1). These hormones act throughout the body to prepare us for responsive action. Epinephrine increases heart rate and blood pressure to help the body meet the new demands. Cortisol increases blood sugar (glucose) to provide more fuel for the energy needed to deal with the stressor, and it does this by promoting the synthesis of glucose and by assisting in the metabolism of fat, protein, and carbohydrates that produce additional glucose. Chronic stress can affect many organ systems and...

Epidemiology and Pathogenesis

Cushing's syndrome account for only 0.2 of all causes of arterial hypertension in the general population, with a prevalence of 1 to 10 cases per million per year.2 Corticotropin-dependent Cushing's syndrome is found in more than 80 of patients. Chronic corticotropin hypersecretion results in hyperplasia of the reticularis and fasciculata zones of the adrenal cortex, with hyperproduction not only of Cortisol but also of deoxycorticosterone and androgens. Two forms of Cushing's syndrome result from increased corticotropin levels pituitary-dependent Cushing's syndrome and ectopic Cushing's syndrome. The second type is corticotropin-independent Cushing's syndrome. Cushing's syndrome may be caused by a unilateral cortisol-secreting adrenocortical adenoma (10 ) or carcinoma (10 ). Primary adrenal hyperplasia is a rare cause of corticotropin-independent Cushing's syndrome. Because adrenocortical tumors secrete increased amounts of Cortisol, corticotropin production is suppressed. In patients...

Miscellaneous Intramedullary Pathology

Other non-neoplastic entities can occur as intramedullary spinal lesions.33,38 Vascular malformations, particularly cavernous angiomas, may occur in the spinal cord. Inclusion tumors and cysts are rarely intramedullary. Lipomas are the most common dysembryogenic lesion and account for approximately 1 of intramedullary masses. These are not true neoplasms but probably arise from inclusion of mesenchymal tissue within the spinal cord itself. They typically enlarge and produce symptoms in early and middle adult years through increased fat disposition in metabolically normal fat cells. Lipomas are often considered juxtamedullary, because they occupy a subpial location.

Gross and Microscopic Appearance

Intracranial lipomas appear as dark-yellow lesions on gross inspection. The meninx primitiva contains within it primitive perivascular reticuloendothelium,6 which may become specialized in the storage of fat, and this may account for the histology of intracranial lipomas. Early precapillary parenchyma may also differentiate into fat cells. Microscopic examination reveals that these lesions are composed of mature adipose cells with peripheral, sometimes indented, small bland nuclei. A col-lagenous capsule that is intimately associated with adjacent brain often surrounds the lipoma. In general, no cleavage plane exists between the tumor and surrounding brain tissue. Histo-logically, although mature fat is the predominant element, variable amounts of fibrovascular tissue, bone, and calcification can also be present. Adjacent parenchymal calcifications and bone formation may occur, although the exact percentage of lipomas showing these changes is not well documented. Bone formation within...

Clinical Trial Methods

Immediate responses that disappear within a short period of time. This includes the fast bronchodilating effect of -agonists, responses to various provocations and specific systemic effects that are measured by markers in the blood (like plasma cortisol for glucocorticosteroids and serum potassium for However, there are caveats with crossover studies. The primary caveat is the possible presence of carry-over effects (in fact, non-equal carry-over effects), which might bias treatment comparisons. When deciding if a crossover design is appropriate for a particular study, we therefore must convince ourself, beforehand, that we can get rid of possible carry-over effects by separating the various treatment periods with washout periods during which no treatment is given. For a single-dose short-acting j2-agonist trial a washout period need in general only be a few days. A trial which studies cortisol depression after short periods of GCS administration should have washout periods of 1 -2...

Integrating Biological Markers and Psychosocial Pathways

Including Cortisol, noradrenalin, epinephrine, and dihydroepiandrosterone (DHEA) (McEwen and Seeman 1999). These primary mediators have widespread influences throughout the body that potentially account for the differential resilience and vulnerability of individuals in response to adverse social circumstances. For example, cortisol is a quintessential stress hormone'' associated with activation of the hypothalamus-pituitary-adrenal (HPA) axis. The dysregulation of cortisol secretion is implicated in a wide range of disease processes, from elevated blood pressure and higher central adiposity to glucose intolerance, immune suppression, and cognitive decline (McEwen 1998). Cortisol measurement has been incorporated into surveys and study designs via 12-hour urine collections and, more recently, noninvasive and relatively inexpensive saliva specimens. In contrast to biological markers like cortisol (which represents one of the primary mediators of the allostatic process), biomarkers of...

The Population Health Perspective

Caldwell's skepticism notwithstanding, a growing number of demographers have been turning their attention toward a broader definition of health beyond simply counting the dead (or living). Without going to the opposite extreme of admitting everything under the WHO definition, health demographers have increasingly turned to more complex outcomes such as cause-specific mortality, disability, self-rated health, health services use, and health behaviors. Problems remain with the accuracy of self-reported health outcomes, but in many large-scale population-based surveys, both demographers and epidemiologists have begun to complement self-reports with biological markers of physiological change (Goldman 2001). Some of these biomarkers (such as salivary cortisol measurements) have only recently become widely available.

Weight Management Motorize Your Metabolism

Weight management is at a crisis level in our country. It is estimated by the U.S. Centers for Disease Control and Prevention that one-third of Americans are 20 percent or more overweight, which qualifies them as being obese. National surveys show that 25-50 percent of adults are on diets and spend about 30 billion each year on them. Unfortunately, a lot of that money goes to waste without the proper lifestyle changes. Two-thirds of those who lose weight will gain it back during the next three to five years. The average human body has 30-40 billion fat cells, which are genetically geared for helping you store unused calories. It's simple Use those calories, or they go into storage visible storage

Can Hormones Be Used To Treat Epilepsy

Endocrine treatment of seizures may rationally be aimed at those endocrino-logic aspects of seizures that act either to exacerbate or to ameliorate them. As already discussed, progesterone may have an anticonvulsant effect, whereas estrogen, CRH, and Cortisol may have proconvulsant effects. Thus, treatment with progesterone, estrogen antagonists, and medications that suppress the activity of the hypothalamo-pituitary-adrenal axis may prove to be useful adjunctive treatments in appropriate patients. As mentioned previously, we have seen three patients with refractory seizures and hypercortisolemia whose seizures became controlled upon normalization of the patients' Cortisol levels by ketoconazole.65 Wider use of ketoconazole and other potential enzymatic inhibitors of Cortisol synthesis has not been explored.

Table 463 Overview Of Immune Function

Cortisol and epinephrine may reduce neutrophil chemotaxis and decrease NK cell activity. 3 Also, perioperative administration of morphine diminishes NK cell and lymphocyte activity. In animal studies, morphine induces a decrease in lymphoid organ weight and inhibits ability to combat active infections. Immunosuppression is not reversed with administration of naloxone. Inhalational anesthetic agents may also inhibit interferon stimulation of NK cell activity. The effect of anesthetic agents on human immune response is unclear and may be clinically significant however, the effects resulting from surgical trauma are probably more important than those of anesthetic agents on postoperative immunosuppression.1

Complications of Radiation Therapy

Radiation therapy results in endocrine dysfunction and visual defects similar to those observed following surgery, but the severity of these complications, particularly with respect to diabetes insipidus, appears to be reduced. In a retrospective study of 72 patients at UCSF from 1972 to 1999 treated for initial disease, 32 had visual deficits after subtotal resection followed by irradiation, although 81 of these had visual deficits before treatment, and 72 retained the same functional status. For 36 patients treated for recurrent disease, only 53 retained the same functional status with no difference associated with extent of surgical resection, whereas 78 had permanent deficits. A majority of patients had impaired endocrine function. Sixty-four percent required thyroid hormone replacement, 56 required cortisol, 44 required sex hormones, 17 had diabetes insipidus, and 1 had elevated prolactin levels. The endocrinologic sequelae of radiation therapy are comparable with other series...

Efficacy Of Peripheral Nerve Block

By interrupting neural input into the CNS, peripheral nerve blocks may also minimize the surgical stress response after surgery. For instance, patients receiving regional anesthesia (interscalene block) for shoulder surgery have significantly lower serum epinephrine levels in the immediate postoperative period.122 Unlike those receiving general anesthesia, patients receiving regional anesthesia (retrobulbar block) for cataract surgery do not have a significant increase in catecholamines, glucose, and cortisol.112 112 Peripheral blocks of the sympathetic nervous system (paravertebral and celiac plexus block) may also blunt but not abolish the stress response.112 112 Systemic absorption of local anesthetic is not likely to be responsible for any suppression of the stress response in the immediate postoperative period.112 Intercostal, intraperitoneal, or intrapleural administration of local anesthetics is not effective in attenuating the stress response.122 1521 152 152 152 Although...

Effects on Acute Phase Response and Cytokines

In a prospective randomized study of laparoscopic versus small-incision open cholecystectomy, Squirrell et al. (20) demonstrated significantly lower C-reactive protein levels following laparoscopic cholecystectomy. However, they found no differences in serum cortisol levels between the two groups and concluded that the neuro-endocrine component of the metabolic response, i.e., cortisol, was not influenced by the type of surgical access (20). These findings were contradicted by McMahon et al. (16), who found no differences in the levels of C-reactive protein or other acute-phase response proteins such as albumin and transferrin between laparoscopic and minilaparotomy cholecystectomy. Because open cholecystectomy in this study was performed through a much smaller incision than would normally be used for open surgical procedures, these results indicate that the trauma of abdominal access influences immunological function. Other studies of laparoscopic versus small-incision...

Are Any Other Hormonal Systems Clinically Affected By Partial Seizures

The function of the hypothalamo-pituitary-adrenal axis may be altered chronically as well as acutely in seizure patients.39,60 Cortisol has been shown to be elevated interictally in some studies61 but not in others.31 Corticotropin is also elevated interictally in patients with temporal lobe seizures,61 a finding that appears to be related specifically to abnormal functioning of the anterior temporal lobe,61 where the amygdala is located, and to be limited to TLE that involves the amygdala. For instance, stimulation of the amygdala in TLE patients62 as well as in animals63 leads to a rise in serum corticosteroids and corticotropin, but stimulation of the hippocampus inhibits their secretion.62 Corticotropin is secreted by the anterior pituitary in response to corticotro-pin-releasing hormone (CRH) produced by neurons in the paraventricular nucleus of the hypothalamus. These neurons receive a direct input from CRH-containing neurons in the amygdala.64 Postictal and interictal elevation...

Is The Checking Of Other Hormone Levels Postictally Worthwhile

Other hormones show less consistent postictal changes. Serum Cortisol is elevated after both bona fide and simulated generalized seizures.39 The Cortisol rise follows that of corticotropin, beta-endorphin, and beta-lipotropin, all products of a common precursor molecule, proopiomelanocortin.6 Elevated vasopressin after seizures has also been reported.60 Because all these hormones are secreted in response to stress, their postictal elevation may not be specific to epileptic seizures. Inconsistent findings of postictal changes in LH and FSH have been revealed by different authors.33-34 60 No consistent significant postictal change has been seen in serum levels of growth hormone or TSH.34,60 Thus, postictal testing of hormones other than prolactin is at present not clinically useful.

Psychosocial Adjustment

Craniopharyngiomas are benign, slow-growing tumors that develop from remnants of the craniopha-ryngeal duct. They are relatively rare and grow in close proximity to the hypothalamus and pituitary. As a result, the tumor disrupts both the endocrine and autonomic nervous systems. Injury to the hypothalamus can produce changes in eating, sleeping, reproduction, and body temperature. Affected connections from the hypothalamus to the limbic system can lead to increased emotionality. Psychiatric disorder is also a consequence of resulting changes in endocrine functioning, as are the alterations in sleeping, eating, and autonomic functioning that frequently accompany hypothalamic injury. Following surgery for craniopharyngioma, nearly 60 of patients experience obesity due to hypothalamic in-sensitivity to endogenous leptin release (Roth et al. 1998). The extent of hypothalamic damage, assessed on magnetic resonance imaging, correlates with the postoperative body mass index. These patients...

DHEA secretion and age

Levels remain very low until they gradually increase between the sixth and tenth years of age owing to increasing DHEA(S) production by the zona reticularis, a phenomenon termed adrenarche (Reiter et al. 1977 Sklar et al. 1980). DHEA(S) concentrations peak during the third decade, followed by a steady decline with advancing age so that levels during the eighth and ninth decade are only 10-20 of those in young adults (Orentreich et al. 1992). This decline has been termed adrenopause in spite of unchanged or even increased cortisol secretion (Laughlin and Barrett-Connor 2000). The age-related decline in DHEA(S) levels shows high interindividual variability and is associated with a reduction in size of the zona reticularis (Parker Jr. etal. 1997). DHEA secretion follows a diurnal rhythm similar to that of cortisol while DHEA(S) does not vary throughout the day. Liu et al. (1990) observed an age-associated attenuation of the diurnal rhythm and the pulse amplitude of DHEA secretion....

Effects on the Developing Brain

The hypothalamic-pituitary-adrenal axis refers to the glands that release substances, such as cortisol, that are known to be elevated in abused children. These substances are also suspected to cause abnormalities in behaviors or phobias such as sleep disturbances and anxiety disorders.

Summary and future directions

Androgens circulate in appreciable amounts in women. Female serum testosterone levels rely on a complex interplay of hormonal secretion and bioconversion of peripheral prehormones. Testosterone levels are proportional to ovarian and adrenal secretion and peripheral bioconversion of the adrenal androgens DHEAS and DHEA, the predominant circulating androgens. Adrenal androgen secretion attenuates with age in a cortisol-independent fashion due to involution of the reticularis zone of the adrenal cortex. As a result, as women age, less testosterone is produced from peripheral bioconversion of DHEAS and DHEA. With the onset of menopause, while ovarian folliculogenesis ceases, the remaining theca and stroma respond to the elevated, menopausal levels of LH by greatly increasing ovarian testosterone secretion. This compensatory mechanism attenuates the age decline in serum testosterone levels from declining adrenal androgens. The combined effects create a subtle decline in serum testosterone...

Evidence Based Treatments

Field et al. (1997) conducted a randomized trial in which youth with mild to moderate JRA who either were massaged by their parents 15 minutes a day for 30 days or engaged in progressive muscle relaxation with their parents daily for 30 days. Findings revealed that the youth in the massage group experienced both psychosocial- and pain-related improvements. Massage immediately reduced parental anxiety, diminished child anxiety based on behavioral observations, and lowered salivary cortisol levels. Long-term massage effects included less frequent pain, lower severe pain, and fewer words for pain. Parent reports indicated less severe pain during the evening and fewer pain episodes limiting vigorous activity, whereas physician reports revealed less pain and less morning stiffness.

Altered neuroendocrine regulation

From the latter studies it can be concluded that alteration in LH secretion in elderly men is not due to increased endogenous opioid tone, whereas the possibility of a relative leptin deficiency as underlying cause has also been excluded (Van Den Saffele etal. 1999). At present, the mechanisms underlying the apparent deficiency of GnRH secretion in elderly men remain to be fully elucidated. The observed changes in LH secretion with decreased mean LH pulse amplitude can be expected to have

Mutations That Raise Blood Pressure

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal dominant trait featuring early onset of severe hypertension caused by a novel gene duplication produced by unequal crossing over between two genes involved in adrenal steroid biosynthesis (Lifton et al. 1992a,b). One of these genes encodes aldosterone synthase, whose enzymatic activity is the rate-limiting step in aldosterone biosynthesis in the adrenal glomerulosa and is normally regulated there by signaling via angiotensin II. The other encodes steroid 11-P hydroxylase, which is employed in cortisol biosynthesis in adrenal fasciculate and whose expression is regulated by adrenocorticotropic hormone (ACTH). These two genes have recently evolved from a common ancestor and are 95 identical in DNA sequence they are tightly linked on chromosome 8, arranged in a head-to-tail orientation. The chimeric gene duplications that cause GRA fuse ACTH-responsive regulatory elements from 11-hydroxylase onto coding sequences that result...

Anterior Pituitary Function

Short Synacthen Test Interpretation

Role in the stress response complicate interpretation of the changes seen in its levels after BSD.121429 Levels of adrenocorticotropic hormone (ACTH) remain within the normal laboratory range after BSD.121430 Cortisol levels may also be 'normal' for non-stressed patients but this may indicate a relative deficiency, which might be uncovered with stress testing (short synacthen test). No relationship between cortisol levels and severe hypotension has been demonstrated.14

Diagnostic Procedures

When Cushing's syndrome is suspected and iatrogenic causes have been excluded, the diagnosis should be confirmed by both an overnight dexamethasone suppression test (1 mg of dexamethasone is given at 11 pm, and a plasma Cortisol measurement is obtained in the morning) and the 24-hour urinary free Cortisol measurement. When the dexamethasone suppression test is normal (plasma Cortisol < 50 mmol L) and the urinary free Cortisol is normal (< 135 nmol 24 hours), the patient does not have Cushing's syndrome. False-positive tests may occur as a result of (1) chronic intake of certain drugs (barbiturates, phenytoin, rifampicin) or alcohol (which accelerates Cortisol metabolism) (2) the presence of a serious illness or stressful event, chronic diseases (renal failure), or major depressive states (which stimulate the secretion of glucocorticosteroids) and (3) obesity and highestrogen states (estrogen therapy, pregnancy), but in the obese patients the urinary free Cortisol is usually...

Obstructive Sleep Apnea

Although obstructive sleep apnea (OSA) is not always associated with obesity, excessive weight is a major risk factor. About 70 of OSA patients are obese. Among obese persons, the incidence of OSA is approximately 40 (Poulain et al., 2006). The increased risk may be related to increased neck circumference and pharyngeal fat deposits. Often unrecognized, OSA has significance beyond daytime somnolence and the spousal impact of disruptive snoring and has been associated with systemic effects as well, such as pulmonary hypertension, right-sided CHF, and erectile dysfunction. Weight loss may benefit the OSA patient. Conversely, a patient with mild OSA who has a 10 increase in body weight then has a sixfold increased risk of progressing to moderate or severe sleep apnea (Caples et al., 2005).

Role of pAdrenergic Receptors in the Regulation of Fat Metabolism

When fed a standard chow diet, P1P2P3-AR-KO mice had a small increase in fat stores when compared with wild-type mice. However, a calorically dense diet, high in fat and sucrose, induced massive obesity in P1P2P3-AR-KO mice. The observed weight gain of 25 g in 8 wk represents the development of extreme obesity and is similar to that observed in leptin-deficient ob ob mice. The marked obesity observed in high calorie-fed P1P2P3-AR-KO mice is caused entirely by a defect in diet-induced thermogenesis (31). These findings establish that P-ARs are required for diet-induced thermogenesis, and that this pathway plays a critical role in the body's defenses against diet-induced obesity. The target tissue mediating sympathetically driven diet-induced thermogenesis is unknown. Although brown adipose has been proposed as the primary target, data from mice lacking UCP1 strongly argue against this. In brown adipose, UCP1 is a downstream component in the generation of heat following sympathetic...

Research Evidence to Date

University-based research found that laughing lowers blood pressure and increases muscle flexibility in addition to releasing endorphins. Endorphins not only reduce pain they also induce a degree of euphoria, and therefore may further enhance the positive effects of laughter. There is also evidence indicating that laughter increases immune activity, and that it can reduce levels of cortisol, a stress hormone associated with suppressing the immune system.

Genetics vs Lifestyle

Single-gene mutations related to obesity often involve leptin and melanocortin. Leptin is a protein produced in adipose tissue that provides negative feedback to appetite control centers. Obesity may reflect lack of hormone production or a lack of leptin receptors. There are leptin-deficient animal models, and rarely, this deficiency has been identified in humans. In leptin-deficient people, weight loss results when leptin is replaced. Leptin supplementation in non-leptin-deficient obese subjects does not result in weight loss (Bray, 2002). Many hormonal factors are involved in appetite, as well as in the absorption, storage, and use of calories. Factors providing input to the brain include leptin levels, vagal afferent activity, Central obesity suggests increased visceral fat deposits, likely caused by increased production of peptides and other metabolic messengers. Hormonal influences most likely play a role in the distribution of fat. Central obesity is believed to result partly...

How Distress Aggravates Pain and Illness

There is little doubt that emotional distress can lower a person's pain threshold and increase pain. Stress also takes a serious physical toll many studies show that stress causes muscles to tighten, disturbs appetite and sleep habits, and triggers the production of stress hormones. These hormones, such as adrenaline and Cortisol, increase heart rate, blood pressure, muscle tension, and blood sugar and, over time, can lower one's pain threshold and weaken the immune response.

Not broken but not working properly

If this were the case, it would be difficult to understand why antidepressant drugs that raise monoamine levels quickly take several weeks to have a significant effect on depressive symptoms. This delay suggests that antidepressants work indirectly and that depression is caused by biochemical dysfunction that is only distantly linked to monoamine function. Indeed, in their search for new targets for antidepressant drugs, pharmaceutical companies are now exploring alternative biochemical pathways, such as those associated with the regulation of the brain's stress hormone cortisol. Growing concerns about the safety and side effects of the monoamine uptake inhibitors are a driving force behind the search for more effective new treatments for this baffling illness of the brain.

Regression Require Commensurate Vascular Remodeling

Studies were conducted using a monogenetic strain of mice (C57BL 6J, ob ob), which develops morbid obesity because of the inability to synthesize leptin (Zhang et al. 1994), a hormone that regulates appetite and metabolism (Pelleymounter et al. 1995 Camp field et al. 1996 Spiegelman and Flier 1996 Halaas et al. 1997). Leptin-deficient (ob ob) mice can gain (or lose, if dieted) nearly 1.0 g d of weight, principally in the form of fat tissue. This far exceeds the average weight changes of 0.1 g d, which are typical of wild-type mice. The substantial shifts in fat mass in ob ob mice provide an opportunity to study the mechanisms coordinating tissue and vascular remodeling. pose tissue loss (Fig. 3). Previous studies showed similar findings (Crandall et al. 1997 Cohen et al. 2001). We further found that the shift from endothelial proliferation to apoptosis occurred under a variety of weight-loss conditions, such as angiogenesis inhibitors, diet restriction, or leptin. This suggests that...

The Goal of Evaluation

Subclinical Cushing

Chiodini and coworkers14 performed a longitudinal study evaluating the rate of spinal and femoral bone loss levels in 24 women with clinically inapparent adrenal masses. They were divided into two groups on the basis of the median value of urinary Cortisol excretion. The group with higher Cortisol values (subclinical Cushing levels) had more lumbar trabecular bone loss than those with low Cortisol secretion (not hypersecreting tumors). Depending on the amount of glucocorticoids secreted, the clinical significance of subclinical Cushing's syndrome ranges from slightly attenuated diurnal Cortisol rhythm to atrophy of the contralateral adrenal gland, a dangerous condition after unilateral adrenalectomy if appropriate therapeutic measures are not taken early enough.37 The best screening test for autonomous Cortisol secretion is the short dexamethasone suppression test. A 2- or 3-mg dose is better than the usual 1-mg dose to reduce false-positive results. A suppressed serum Cortisol (< 3...

Clinically Inapparent Adrenal Mass Incidentaloma or Adrenaloma

Recently, at a State of the Science Conference at the National Institutes of Health Conference, the term clinically inapparent adrenal mass was coined.3 The widespread teaching is that most adrenalomas are indolent tumors, nonfunctioning and asymptomatic, causing no harm to the patient.4 5 Recent studies, however, have shown that a high percentage of these tumors can be subclinically functioning, causing symptoms milder than those encountered in the well-known adrenal-hyperfunctioning syndromes but still harmful to the patient.614 Thus, the screening tests of serum potassium, urinary vanillylmandelic acid (VMA), and serum Cortisol do not suffice and more detailed and in-depth laboratory investigation is necessary. The fear of adrenal carcinoma that dictated the approach to these tumors in the past (with the main emphasis on the size of the tumor) should be changed to the fear of the subtle function of these usually benign adrenal cortical adenomas with coexistent metabolic pathology...

Physiologic Effects of Corticosteroids

Cortisol Cortisol exerts its effect by regulating gene transcription after binding to glucocorticoid receptors within the cell.9 Cortisol has a large number of metabolic effects on several tissues. However, many of the effects of glucocorticoids are based on studies of patients, animals, and cells with non-physiologically high or low levels of glucocorticoids. Glucocorticoids are necessary for maintaining hepatic glycogen stores. They stimulate protein catabolism and lipolysis and cause hyperinsulinemia.1 Cortisol is required for maintenance of normal blood pressure. The effect on immunologic function of glucocorticoids in physiologic levels is not clear, but glucocorticoid excess suppresses both immunologic and anti-inflammatory responses. Glucocorticoids have a weak mineralocorticoid effect and influence calcium homeostasis by decreasing intestinal calcium absorption and increasing urinary calcium excretion.1 In pharmacologic doses, Cortisol causes osteoporosis. The effects of...

Adrenal insufficiency

Adrenal insufficiency refers to impaired secretion of cortisol with or without impaired secretion of aldo-sterone. Adrenal insufficiency can result from disorders of the adrenal cortex (primary adrenal insufficiency) or of the hypothalamus or pituitary (secondary adrenal insufficiency) (see Figure 19-2). Symptoms of adrenal insufficiency include weakness, abdominal pain, and hyperpigmentation. Chronic primary adrenal insufficiency, or Addison's disease, usually results from autoimmune adrenali-tis and can be treated with cortisol and aldosterone replacement.

Definition and Pathogenesis

Insulin is also important in maintaining the integrity of proteins, whose amino acids become substrates for hepatic gluconeogenesis when cortisol and glucagon's actions are unopposed by insulin. Insulin insufficiency of diabetic disorders has ubiquitous adverse effects on metabolism of all energy substrates, which contributes to the diverse complications challenging diabetic patients in their activities of daily living.

Physiological Transport Mechanisms for Peptides and Proteins at the Blood Brain Barrier

The concept of saturable, receptor-mediated uptake systems for peptides and proteins at the blood-brain barrier has evolved over the last two decades. There is now combined evidence from in vitro and in vivo studies, at the biochemical and pharmacokinetic levels as well as at the morphological level, that peptides are transported across the endothelial cells. This includes transport of compounds as structurally diverse as insulin and insulin-like growth factors (IGF-I and II) (56), transferrin (57), low density lipoprotein (LDL) (58), and leptin (59). The overall process of transendothelial passage is designated as transcytosis and is composed of binding to a luminal plasma membrane receptor, endocytosis, transfer through the endothelial cytoplasm to the abluminal side, and abluminal exocytosis into brain interstitial space (60). Recently, substantial evidence has been accumulated to support the presence at the BBB of a transport system that is involved in the transcytosis of leptin....

TABLE 714 Evaluation of the Patient with Suspected Cushings Syndrome

24 h urinary free cortisol-values greater than 3 times the ULN are highly sensitive and specific. Values between ULN and 3 times ULN require repeat testing and clinical judgment depending on the level of suspicion Overnight dexamethasone suppression test-One mg given between 11 pm and midnight followed by an 8 am serum cortisol. Serum cortisol should suppress to < 1.8 J.g dL in normals Late evening salivary cortisol less than 1.3 ng mL in normals this test is becoming increasingly popular because of its ease of collection and stability of cortisol in saliva at room temperature Late night plasma ACTH and cortisol (11 pm-midnight)-Serum cortisol should be > 15 J.g dL ACTH < 10 pg ml-ACTH-independent process, ACTH > 20 pg ml ACTH-dependent process High dose dexamethasone suppression test-2mg every 6 h with 24 h urines collected for free cortisol and 17-hydroxysteroids suppression is compatible with a pituitary adenoma free cortisol should suppress > 90 and 17-hydroxysteroids...

TABLE 713 ClResistant Metabolic Alkalosis with Hypertension Suppressed Aldosterone Levels Acquired Disorders

Most corticosteroids (specifically cortisol, deoxycorticosterone, and corticosterone) also have significant mineralocorticoid effects and produce hypokalemic metabolic alkalosis Collecting duct cells contain type II 11 3-HSD that degrades cortisol to the inactive metabolite cortisone cortisol secretion in response to ectopic ACTH may be so high, however, that it overwhelms the metabolic capacity of the enzyme in addition, type II 11 fi-HSD may be inhibited by ACTH This chemical inhibits type II 11 -hydroxysteroid dehydrogenase activity and uncovers the mineralocorticoid receptor which is normally protected by this enzyme from glucocorticoid stimulation hydroxysteroid dehydrogenase

Adrenocorticotrophic hormone stimulation test

This is used to aid the diagnosis of Cushing's disease (Fig. 22.14) or of Addison's disease, which is hypoadrenocor-ticalism. Adrenocorticotrophic hormone (ACTH) is normally secreted by the pituitary gland to stimulate the secretion of cortisol from the adrenal cortex. A blood sample is taken and cortisol levels are measured. A synthetic ACTH, e.g. Synathacon, is then administered intravenously and blood cortisol levels are measured again within 60-90 min of the injection.

Other Phenotypes in the Adrenergic Receptor Knockouts

The D KO had a very interesting increase in daily food and water intake, which might in part have been related to chronic hypotension (17). The B KO had a variety of abnormalities of glucose metabolism, including insulin resistance, increased plasma leptin, increased percentage body fat (with no change in body weight), and glucose intolerance and obesity with a high-fat diet (12). The authors offered an explanation involving increased parasympathetic activity caused by increased hypothalamic neuropeptide Y (12), and certainly further work in this area will be interesting and important. A current clinical paradigm is that a1-antagonists decrease insulin resistance, the opposite of the B KO. INC plasma leptin (12) INC body fat (12) Insulin resistance (12)

Intergenerational Transmission

In a study of risk factors for the development of PTSD, Yehuda and her colleagues examined the association between cortisol and PTSD in children of holocaust survivors. Low cortisol levels were significantly associated with both PTSD in parents and lifetime PTSD in subjects, whereas having a current psychiatric diagnosis other than PTSD was relatively, but nonsignificantly, associated with higher cortisol levels. Offspring with both parental PTSD and lifetime PTSD had the lowest cortisol levels of all study groups. They concluded that parental PTSD is associated with low cortisol levels in offspring, even in the absence of lifetime PTSD in the offspring. They suggested that low cortisol levels in PTSD may constitute a vulnerability marker related to parental PTSD as well as a state-related characteristic associated with acute or chronic PTSD symptoms (Yehuda et al., 2000).

Clinical implications

Exogenous androgens induce both apparently beneficial and deleterious effects on cardiovascular risk factors by decreasing serum levels of HDL-C, PAI-1 (apparently deleterious) Lp(a), fibrinogen, insulin, leptin and visceral fat mass (apparently beneficial) in men as well as women. However, androgen-induced declines in circulating HDL-C should not automatically be assumed to be pro-atherogenic, since they may reflect accelerated reverse cholesterol transport instead.

Variation in the androgen receptor

A variable number of CAG repeats in exon 1 of the androgen receptor gene on the X-chromosome, which normally ranges between 9 and 35 encodes for a variable number of glutamine residues in the aminoterminal domain of the receptor and is inversely associated with the transcriptional activity of testosterone-responsive target genes. Abnormal expansion of the CAG repeats beyond the number of 36 leads to Kennedy disease, which is accompanied by signs of hypoandrogenism (see Chapter 2 for details). Within the physiological range of 9 to 35, the number of CAG repeats was shown to be inversely associated with the risk of prostate cancer, benign prostatic hyperplasia, sperm production, and bone density, and depression (Dowsing et al. 1999 Ferro et al. 2002 Seidmann et al. 2001 von Eckardstein et al. 2001 Zitzmann et al. 2001a). With respect to cardiovascular disease it is important to emphasize that the number of CAG repeats is positively correlated with flow-mediated vasoreactivity and...

Temperature regulation

A combination of an underdeveloped thermoregulatory system, minimal subcutaneous fat deposits and a high body surface area to volume ratio increases the potential risk of significant heat loss in neonatal patients so maintaining a warm environmental temperature is essential. The temperature for the first 7 days should be 29 C, decreasing to 26 C for

Classification And Clinical Presentation

Cushing's disease, elevated serum ACTH and Cortisol levels Corticotrophic adenomas often present a diagnostic dilemma for clinicians, because their imaging characteristics and laboratory abnormalities are variable. Tumor size appears to have no correlation with severity of hypercortisolism, and the tumor is often not seen on imaging studies before surgery. Thus in all patients a thorough laboratory investigation must be performed to confirm the diagnosis preoperatively, especially where tumor is not obvious on imaging studies. Determinations of serum cortisol, adrenocorticotropic hormone (ACTH), 24hour urine free-cortisol, high- and low-dose dexamethasone

Intravenous Local Anesthetics

Have looked at the effect on the stress response. Incisional application of lidocaine with an aerosol provides long-lasting pain relief as well as inhibition of the P-endorphin response.1 Incisional infiltration with bupivacaine may prevent the cortisol and glucose response to herniotomy but may not modify the leukocytic or acute phase response, even in patients whose wounds are cooled to about 15 C.13 No studies are available concerning the use of local anesthetic creams on the wound postoperatively. In summary, the limited data suggest modification of some aspects of the stress response by application of local anesthetics to the wound. However, the effect is small and short-lasting comparable to the short-lasting pain duration.

Adrenal Cortex And Medulla

Polypeptide Chain Cortex

The cortex consists of three distinct zones. The outer zona glomerulosa, which is made up of whorls of cells, merges into the zona fasciculata formed of columns of cells with prominent venous sinuses. This layer merges into the inner zona reticularis made up of a network of cells (Fig. 28.2). These cells are abundant in lipid, which reflects the fact that they synthesize and secrete lipid hormones. All the cells secrete corticosterone, but the enzymes responsible for aldosterone synthesis are found only in the zona glomerulosa. The enzymes for Cortisol and sex hormone synthesis are found in the zona fasciculata and zona reticularis. The zona glomerulosa also forms the new cortical cells, which allows regeneration. The adrenal medulla cannot regenerate. All the steroids are secreted as the free steroid, except for dehy-droepiandosterone (DHEA) which is conjugated to sulphate. Cortisol and corticosterone are the main glucocorticoids secreted, with a ratio of 7 1. The principal...

Nonpharmacologic Therapy

Ism can result in prolonged adrenal insufficiency lasting for months after surgery and requiring exogenous glucocorticoid administration. Pituitary irradiation or bilateral adrenalectomy is usually reserved for patients who are not surgical candidates or for those who relapse or do not achieve complete remission following pituitary surgery. Because the response to pituitary irradiation can be delayed (several months to years), concomitant treatment with cortisol-lowering medication may be necessary. Bilateral adrenalectomy is also used for the management of adrenal carcinoma and in patients with poorly controlled ectopic Cushing's disease in whom the ACTH-pro-ducing lesion cannot be localized. Bilateral laparoscopic adrenalectomy achieves an quire lifelong glucocorticoid and mineralocorticoid supplementation. ' Nelson's syndrome may develop in nearly 20 to 50 of patients who undergo bilateral adrenalectomy without pituitary irradiation. This condition presumably results from...

Treatment and outcome evaluation Chronic Adrenal Insufficiency

Scribed because it most closely resembles endogenous cortisol with its relatively high mineralocorticoid activity and short half-life, and allows the design of regimens that simulate the normal circadian cycle.5 Other glucocorticoids, however, can be used. The pharmacologic characteristics of commonly used glucocorticoids are presented in Table 45-3.4 Since patients with primary adrenal insufficiency can experience DHEA deficiency, DHEA replacement also has been tried. Several small clinical studies, consisting mostly of women, suggest that treatment with DHEA can improve mood and fatigue and provide a general sense of well-being.10-13 Nonetheless, use of DHEA remains controversial and requires further study. The specific management strategies for chronic adrenal insufficiency are as follows2,5,9 For the treatment of primary adrenal insufficiency (Addison's disease), oral hydrocortisone 12 to 15 mg m is typically administered in two divided doses, with two-thirds of the dose given in...

Regional and General Anesthesia and Surgical Stress

Of certain stress hormones, like adrenaline and Cortisol, by the adrenal gland. These hormones can be detrimental to the body in a great number of ways when they persist for extended periods. The release of adrenaline alone increases heart rate, blood pressure, and oxygen demands on the heart, which may be harmful or fatal in the patient with advanced heart disease. It also causes elevated blood glucose levels and can impair the immune response, increasing susceptibility to infection.

Circadian Dysregulation

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most reproducible biomarkers of major depressive disorder (reviewed in Holsboer, 2000). Increases in urinary cortisol production, levels of corticotropin-releasing hormone (CRH) in spinal fluid (Nemeroff, 1996), and a general disturbance in the normal pattern of cortisol secretion have been identified (Carroll et al., 1981). Blunted suppression of morning cortisol levels following oral dexam-ethasone administration, the so-called dexamethasone suppression test (DST), was previously considered a specific marker of depressive illness. It is now recognized as an abnormality in only some subsets of depressed patients, notably psychotic depressives. Also reported is blunted adrenocorticotrophic hormone (ACTH) response to exogenous CRH. More sensitive to detect HPA dysregulation is the combined use of the DST and the CRH stimulation test. In the setting of an abnormal HPA axis test, clinical...

Stressful Life Events

Stressful life events, including childhood trauma, have been associated with the development of som-atization later in life (Campo and Fritsch 1994). Chronic stressors can have an effect on the body's stress response systems, such as the hypothalamic-pituitary-adrenal (HPA) axis. Although elevations of cortisol may be associated with acute stress, prolonged exposure to stress can suppress the HPA axis, resulting in the lowered cortisol levels that are associated with somatic complaints (Lackner et al. 2004). Somatoform symptoms have been linked to traumatic events experienced in both childhood and adulthood (Binzer et al. 1997 Roelofs et al. 2002). Roelofs et al. (2005) have found that the number of traumatic events an individual has experienced is associated with the number of conversion disorder symptoms exhibited. Of traumatic events experienced, those pertaining to relationship and occupational problems are most likely to trigger immediate somatic symptoms in adults (Roelofs et...

Endocannabinoid Blockers

Wild-type animals, CB1-knockout mice have leaner body composition, but this lean phenotype is not fully explained by changes in food intake. Stimulation of the CB1 receptors in fat cells promotes lipo-genesis and inhibits the production of adiponectin, a cytokine derived from adipose tissue that has potentially important antidiabetic and antiatherosclerotic properties.59 The system may provide a possible treatment target for high-risk overweight or obese patients.

Chemistry of Insecure Attachment

Instead of the warm and fuzzy feelings activated by oxytocin, stress chemicals are triggered. Cortisol, the chemical that keeps us alert and helps us deal with stress, seems to be the main culprit at work here. Sometimes cortisol is necessary, for example, in the morning when its concentration is highest to help us wake up. But cortisol's dampening effect on oxytocin is a less positive thing when you wish to be calm and open to human connection. Either of these lifelong positive and negative biochemical patterns begins in baby's first year.

Neuroendocrine Responses to Stress

The hypothalamic-pituitary-adrenal (HPA) axis is one of the most widely studied of the stress responsive systems. This cascade begins with the release of CRH from the parvocellular neurons of the paraventricular nucleus of the hypothalamus into the external zone of the median eminence. From here CRH is carried through the portal blood system to the anterior lobe of the pituitary gland, where it acts as a secretagogue for adrenocorticotrophic hormone (ACTH). ACTH is then released into the systemic circulation and carried through the blood to the adrenal cortex, where it stimulates cells in the zona fasciculata to produce and release glucocorticoids. The glucocorticoid released in response to stress in the rat is corticosterone (CORT), while the human adrenal cortex secretes cortisol. Since corticosterone and cortisol vary only slightly in their chemical structure, both are classified as glucocorticoid hormones and bind to the same receptors in the body with comparable affinity. It is...

Circulating factors that influence bone cell function

More recently, a mechanism of hypothalamic control of bone metabolism has been demonstrated. In contrast to the metabolic pathways of PTH and vitamin D, factors are secreted by bone cells and then themselves in turn affect overall bone metabolism through a centrally mediated mechanism. Leptin, a small polypeptide hormone, is secreted by osteoblasts. Its direct effects are thought to be through control of body weight, while its indirect effects may be through modification of gonadal function via interactions within the hypothalamus 1 . In animal studies, mice with leptin deficiency demonstrated obesity, hypo-gonadism, and increased bone formation and bone mass. This newly discovered interrelationship between the central nervous system and bone metabolism offers an exciting new frontier in the understanding and possible treatment of metabolic bone disorders such as osteoporosis.

Dermis and hypodermis

The dermis is rich in blood vessels, lymphatic vessels, and nerve endings. An extensive capillary network connects to the systemic circulation with substantial horizontal branching from the arterioles and venules in the papillary dermis. These in turn form plexus and supply capillaries to the hair follicles and the glands. The lymphatic vessels serve to drain the excess extracellular fluid and clear the antigenic materials. The dermis is filled with scattered fibroblasts, macrophages, leukocytes, and mast cells, in addition to the hair follicles, sebaceous glands, and sweat glands. On average, about 10 hair follicles, 15 sebaceous glands, 12 nerves, 100 sweat glands, 360 cm of nerves, and three blood vessels are present in one square centimeter of skin (Barry, 1983). The hypodermis constitutes the deepest layer of the skin, and consists of the subcutaneous tissue filled with fat cells, fibroblasts, and macrophages.

Reproductive system Male or buck

The bicornuate uterine tract has evolved to produce large litters of young and consists of two long uterine horns, each of which enters the vagina via its own cervix. There is no uterine body. The mesometrium that suspends the tract within the peritoneal cavity contains abundant amounts of fat and is a major fat storage area.

A role for milk in the control of mammary function in the tammar wallaby

The expression of milk protein genes is regulated concurrently by systemic endocrine factors, by paracrine factors such as the extracellular matrix and by autocrine factors secreted in the milk. Previous studies using a tammar wallaby mammary explant culture model (Nicholas and Tyndale-Biscoe, 1985) have shown that different combinations of insulin, cortisol and prolactin are required for expression of the a- and -casein genes, and whey protein genes including a-lactalbumin and -lactoglobulin (Simpson and Nicholas, 2002). Tammar wallaby mammary explants from late pregnant tammar wallabies can be induced with insulin, cortisol, prolactin, thyroid hormone and oestrogen to express the WAP gene (Simpson et al., 2000). Therefore, the inhibition normally observed in vivo during Phase 2A, and the subsequent induction of WAP gene expression around 100 days post-partum, may be hormonally regulated. In addition, the LLP genes can be down-regulated in mammary explants from Phase 3 tammar...

Hormonal changes with exercise

During exercise, several hormonal systems are activated and increases are seen in plasma concentrations of adrenaline noradrenaline (epinephrine norepinephrine), adrenocorticotrophic hormone (ACTH), cortisol, b-endorphin, growth hormone, renin, testosterone, thyroid hormone and several gastrointestinal hormones (Fig. 1.2.4). Arterial levels of glucagon are unchanged or only marginally increased

Hormonal regulation of resting metabolism

Insulin stimulates glycogen synthesis in the liver and also promotes liver glucose uptake, but only at an elevated portal vein glucose concentration. Glycogen synthesis in the liver is also directly stimulated by increased vagal nerve activity. Glucagon, on the other hand, stimulates hepatic glycogenolysis as well as lipolysis in adipose tissue. In addition, glucagon stimulates the liver capacity for gluconeogenesis. The effect of glucagon on adipose tissue lipolysis is, however, secondary to the more powerful stimulation by the sympathetic nervous system, cortisol and growth hormone. Several other factors may stimulate hepatic glycogenolysis, including a- and b-adrenergic stimulation and vasoactive intestinal polypeptide, whereas hepatic gluconeogenesis is stimulated by increased precursor (lactate, pyruvate, amino acids, glycerol) availability, secondary to skeletal muscle glycolysis, skeletal muscle proteolysis and adipose tissue lipolysis. During exercise all these processes are...

Metabolism of testosterone

Testosterone Metabolism

Isoforms of5a-reductase exist and isoform 2 is most important because deficiencies of reductase type 2 are correlated with abnormal clinical manifestations (Wilson etal. 1993). To establish a critical steady state concentration ofDHT, not only the activity of the 5a reductase must be high enough, but also the metabolism ofDHT must be low. In the prostate of the dog the activity of the reductive 3a 3 - steroid dehydrogenase activities are low, and this favours the formation ofDHT. The low rate of metabolism through the 3a 3 - dehydrogenase pathway may be the consequence of a low expression of one or both of these enzymes in the prostate, but it may also be possible that within one cell there is a balance between oxidative and reductive actions of two different iso-enzymes. Support for this hypothesis is a report showing that rat and human prostate contain an oxidative 3a-hydroxysteroid dehydrogenase that can convert 5a-androstane-diol back to dihydrotestosterone (Biswas and Russell...

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