Cortisol deficiency

Cortisol deficiency after abrupt cessation of administration... 

Cortisol deficiency results in impaired renal function (particularly glomerular filtration), augmented vasopressin secretion, and diminished ability to excrete a water load. 

The THEiTHF + 5aTHF ratio is commonly greater than 15 in these disorders, the opposite to AME syndrome. While the ratio of saturated steroids demonstrates a high 11-oxo l 1/1-hydroxy ratio, this is not the case for steroids retaining a - -4-ene structure. The F E ratio is normal or elevated (i.e., > 1 Table 5.3.9). Steroid profile analysis also typically reveals an elevated excretion of DHEA and other androgen metabolites. Clearly the excessive ACTH production resultant from an apparent cortisol deficiency is responsible for the elevated adrenal androgen production, which in turn is responsible for female virilization and other manifestations of polycystic ovary syndrome. 

Patients with virilizing hyperplasia of the adrenal have a relative cortisol deficiency due to a block in normal synthesis, and this deficiency may be detected only during the demands of a surgical procedure. 

A rare form of adrenal insufficiency probably caused by an unresponsiveness to ACTH with cortisol deficiency and normal secretion of aldosterone, deoxycorticosterone and corticosterone probably as the result of a missing enzyme on the part of cortisol has been reported. The syndrome is inherited in some cases as an autosomal in others as an X-linked trait. It is associated with (1) undetectable levels of corticosteroids in plasma, (2) a failure to respond to ACTH infusion, (3) normal electrolytes with low salt diet [83]. 

Cortisone Reductase DeGciency. In hirsutism and virilization in females, cortisone reductase deficiency has been described. Patients with this disorder convert all their cortisol into cortisone. This gives rise to an apparent cortisol deficiency. Adrenocorticotropic hormone increases and stimulates the adrenal steroid synthesis. The urinary steroid profile is characterized by a very high excretion of THE, cortolones, and adrenal androgens, and low excretion of THF and 5a-THF [33]. 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

Congenital adrenal hyperplasia A rare inherited condition resulting from a deficiency in cortisol and aldosterone synthesis with resulting excess androgen production. The clinical presentation depends on the variant of the condition, but it typically manifests as abnormalities in sexual development and/or adrenal insufficiency. 

Primary adrenal insufficiency (Addison s disease) most often involves the destruction of all regions of the adrenal cortex. There are deficiencies of cortisol, aldosterone, and the various androgens. Medications that inhibit cortisol synthesis (e.g., ketoconazole) or accelerate cortisol metabolism (e.g., phenytoin, rifampin, phenobarbital) can also cause primary adrenal insufficiency. 

In relatively recent years, it has become clear that under-nntrition of mother leads to low birth weight of the baby and this can increase the risk of development of degenerative disease in later life, e.g. hypertension, obesity, type 2 diabetes. One hypothesis is that the foetus adapts meta-bolically to deficiencies by increasing the number of cells in organs that perform specific functions that can overcome the deficiency, e.g. an increase in the number of liver cells that carry out gluconeogenesis, an increase in cells in the adrenal cortex to produce more of the chronic stress hormone, cortisol. These changes are carried over into adnlthood which can lead to an inadequate response of the liver to insulin so that insulin resistance develops. So far, however, it is unclear whether deficiencies in specific nntrients or undemutrition per se are responsible for snch changes (Chapter 15). 

Addison s disease), both cortisol and aldosterone must be replaced when ACTH production is deficient (secondary AC insufficiency), cortisol alone needs to be replaced. Cortisol is effective when given orally (30 mg/d, 2/3 a.m., 1/3 p.m.). In stress situations, the dose is raised by 5- to 10-fold. Aldosterone is poorly effective via the oral route instead, the mineralocorticoid fludrocortisone (0.1 mg/d) is given. 

In the treatment of secondary adrenocortical insufficiency, lower doses of cortisol are generally effective, and fluid and electrolyte disturbances do not have to be considered, since patients with deficient corticotrophin secretion generally do not have abnormal function of the zona glomerulosa. Since cortisol replacement therapy is required for life, adequate assessment of patients is critical to avoid the serious long-term consequences of excessive or insufficient treatment. In many cases, the doses of glucocorticoid used in replacement therapy are probably too high. Patients should ideally be administered three or more doses daily. To limit the risk of osteoporosis, replacement therapy should be carefully assessed on an individual basis and overtreatment avoided. 

Congenital enzymatic defects in the adrenal biosynthetic pathways lead to diminished cortisol and aldosterone production and release. In these conditions, corticotrophin secretion is increased, and adrenal hyperplasia occurs, accompanied by enhanced secretion of steroid intermediates, especially adrenal androgens. More than 90% of cases of congenital adrenal hyperplasia are due to 21-hydroxylase deficiency, which is cre-afed by mufafions in fhe CYP21 gene encoding fhe en-... 

The steroid-inhibiting properties of metyrapone have also been used in the treatment of Cushing s syndrome, and it remains one of the more effective drugs used to treat this syndrome. However, the compensatory rise in corticotrophin levels in response to falling cortisol levels tends to maintain adrenal activity. This requires that glucocorticoids be administered concomitantly to suppress hypothalamic-pituitary activity. Although metyrapone interferes with lip- and 18-hydroxylation reactions and thereby inhibits aldosterone synthesis, it may not cause mineralocorticoid deficiency because of the compensatory increased production of 11-desoxycorticosterone. 

Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregnenolone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. The enzymes and cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. 

HD 21 -Hydroxylase deficiency 5PT 5-pregnene-3/ ,17a,20a-triol, 160HDHEA 16a-hydroxyDHEA, 17HP 17a-hydroxy-pregnanolone, d days, Fs cortisol metabolites, m months, yrs years, Pat patient, PTONE pregnanetriolone... 

Reports on serum steroids in affected patients (not analyzed by LC-MS) show elevated 17-OHP and low testosterone concentrations. In order to prevent confusion of this condition with 21- or 17-hydroxylase deficiency, the following panel of steroids should be analyzed 17-OHP, 21-deoxycortisol, corticosterone, progesterone, and pregnenolone all of which should be elevated. Cortisol should be normal and testosterone and DHEA (including sulfate) low for age. Patients show a blunted cortisol response to ACTH stimulation. 

Patients with 11/1-hydroxylase deficiency present with features of androgen excess, including masculinization of female newborns and precocious puberty in male children. There are two human isozymes that are responsible for cortisol and aldosterone synthesis, respectively. The CYP11B1 enzyme (p45011B) converts DOC to corticosterone (B) and 11-deoxycortisol (S or 11-dihydrocortisol) to cortisol (F). It is also capable of 18-hydroxylating DOC but cannot convert to aldosterone. The latter transformation is carried out by CYP11B2 (also known as aldosterone synthase), which encompasses activity for 18-hydroxylation and subsequent 18-oxidation. When CAH is associated with hypertension, deficient lljS-hydroxylase (CYP11B1) is suspected at this time more than ten mutations have been defined in affected individuals [103]. 

This condition was first noted in two markedly hirsute sisters who had elevated production of cortisol but were not Cushingoid [66]. It was found that these patients had elevated excretion of THE and related 11-oxo-steroids relative to 11/Lhydroxy-lated compounds, and so the disorder was named apparent cortisone reductase deficiency (ACRD). Subsequently, the disorder has been documented in other patients (Table 5.3.8) [3,15, 38, 54]. Presumably, the rapid and irreversible conversion of cortisol to cortisone protects against some of the negative manifestations of hypercor-tisolism. Hyperandrogenism secondary to increased cortisol clearance is the most serious clinical manifestation of the condition. 

Infants with salt-losing crisis and adrenal insufficiency in infancy may have adrenal hypoplasia congenita. This can be of two types recessive, for which the cause has not been defined and which affects mostly the fetal zone, and X-linked, which is caused by mutations in the DAX-1 gene, which (with steroidogenic factor-1) controls definitive zone development and steroidogenesis [71]. GC-MS analysis of patients with the disorder show variant patterns from absence of neonatal A5 steroids, appropriate for the recessive form [81], to extremely low cortisol production and transient 11/Lhy-droxylase deficiency, as evidenced through increased THS excretion (Malunowicz, personal communication). 

Absence of the C-21 hydroxylase is one of the commonest of hereditary metabolic defects and is one of several enzymatic deficiencies that lead to congenital adrenal hyperplasia.265-269 Cortisol, the synthesis of which is controlled by ACTH, is secreted by the adrenals in amounts of 15-30 mg daily in an adult. 

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