Heim C, Ehlert U, Hellhammer DH



Cortisol

• For primary adrenal insufficiency: Check adrenal cortex antibodies and steroid 21-hydroxylase abs.

• Primary cortisol deficiency causes hyponatremia because ADH is co-secreted with CRH, leading to water retention. Decreased vascular tone (cortisol sensitizes vessels to catecholamines) leading to relative hypotension also stimulates ADH. Aldosterone deficiency causes sodium wasting and potassium retention.

• Cortisol production rates are 2x higher in men than women, and free cortisol levels are higher in men than in women (Vierhapper 1998, Purnell 2004), this is one factor explaining women’s much greater incidence of mild-moderate cortisol insufficiency. Another factor is inhibition of 11beta HSD type 1 levels and action by estradiol. (Cohen 2005)

• Estradiol inhibits adrenal production of cortisol by inhibiting 3 beta hydroxysteroid dehydrogenase. This provides a mechanism for elevated estrogen to cause cortisol deficiency, allergies and autoimmune diseases. (Gell, 1998)

• Estradiol given to post-menopausal women causes a decline in cortisol levels (Kerdelhué 2006)

• Women make half the cortisol that men do. (Vierhapper, 1998)

• PCOS patients have reduced urinary 11 OH/11 oxo ratios indicating decreased cortisol activity which can cause increased ACTH causing increased DHEAS. This could be one mechanism by which PCOS is produced.

• Williams Textbook 10th Ed. P. 508: suppression of the HPA axis is invariable in patients taking the equivalent of 15mg or more of prednisolone per day chronically…variable with 5 to 15mg/day, reported in some cases at 5mg/day, but clinically significant suppression at 5mg is debatable. (Danowski 1964) 5mg to 7.5mg prednisolone (and prednisone) is considered a physiological dose. (5mg of prednisolone is a bit more potent than 20mg hydrocortisone-HHL).

• “primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant'.” (Lamberts 1996) (due to one of two point mutations in the glucocorticoid receptor gene-UpToDate)

• “In general, the adrenal gland produces about 50 mg/day of cortisol during a minor procedure or surgery (normal basal secretion is 8 to 10 mg/day), while 75 to 100 mg/day are produced with major surgery. The cortisol secretion rate can reach 200 to 500 mg/day with severe stress, but secretion rates greater than 200 mg/day in the 24 hours after surgery are rare.” (UpToDate) How about severe mental stress?-HHL

• “Included in the intermediate group is any patient who has taken less than 10 mg of prednisone or its equivalent (less than 40-50mg cortisol) per day, providing that it is not taken as a single bedtime dose for more than a few weeks. Although a few such patients may have inadequate responses to metyrapone, low-dose ACTH, or hypoglycemia for brief intervals after cessation of therapy, the incidence of clinical adrenal insufficiency is exceedingly low. (UpToDate—“Pharmacologic Uses of Glucocorticoids”)

• Endogenous production is estimated at 5 – 10mg/m2/day, or between 8 and 16mg for average sized women and between 10 and 21mg for average-sized men. Oral replacement cortisol dose is 12-15mg/m2/day or 20 to 30mg/day. Doses of 16mg/m2 have been associated with bone loss in adults (without DHEA supplementation). Doses greater than 17mg/m2/day have been associated with reduce height in CAD patients. (Bonfig 2009)

• Women on estrogen/progestin and prednisone doses of 5 to 15mg actually gained bone mass. (Lukert 1992). (Equiv. to hydrocortisone doses of 25-60mg daily)

• Appropriate dose by subcutaneous hydrocortisone infusion, determined by saliva and serum testing, was found to be 10mg/m2/day (Lovas). Oral dose is approximately double the infusion dose due to inefficient absorption, liver metabolism, etc. Some persons require 18mg/m2/day by infusion (Bryan 2009)

• BSA (m²) = ( [Height(in) x Weight(lbs) ]/ 3131 )½ ,( [Height(cm) x Weight(kg) ]/ 3600 )½

• Partial adrenal suppression with reduced ACTH stimulation test response can be seen with doses of 20-30mg hydrocortisone/day in some adults (not corrected for thyroid or DHEAS levels).

• 20mg HC daily did not increase insulin resistance compare to a physiological HC infusion (McConnell, 2002).

• Some significant adrenal suppression (fails ACTH stim. Test) seen in hydrocortisone doses of 16mg/m2/day or 20+5 to 30+5mg/day (not corrected for thyroid or DHEAS levels). (McKenzie, 2000)

• Bliesner: There’s more to cortisol dosing than mg/day! 5mg qid will give a ~20% lower 24 hr. free cortisol urinary secretion than 10 bid (other studies indicate that larger, fewer doses also produce more adrenal suppression—a peak effect like with thyroid/TSH).

• One mg of prednisolone is said to equal to 4 mg of hydrocortisone. However, their ratio in producing growth suppression is 1:15 ! (Punthakee)

• One mg of prednisone is said to equal 4mg of hydrocortisone, however, 7.5mg of prednisone produced much more bone loss than 30mg of hydrocortisone, so the ratio is probably more like 1:5 or 1:6. (Jodar)

• One mg of methylprednisolone is said to be equivalent to 5mg HC, but infusions of each hormone with these ratios showed that the MP caused insulin levels to rise twice as high as with HC (Bruno, 1994)

• 0.5mg of dexamethasone is said to be equal to 20 mg of hydrocortisone. Yet 0.5mg dexamethasone caused 50% worse insulin insensitivity, 50% greater islet beta cell function, and a 50% greater change in bone resorption markers than 20mg hydrocortisone. (Suliman) The ratio here is probably more like 70mgHC=1mg Dexamethasone. (In that same study, 10+5+5 produced slightly lower cortisol-effect parameters than 10+5mg?).

• AM cortisol 200 nmol/l but a peak stimulated cortisol < 500 nmol/l and 10 matched healthy male control volunteers participated. DESIGN: Patients were assigned, in a random order, to a cross-over protocol of treatment for 1 week with full dose hydrocortisone (10 mg twice daily), half-dose hydrocortisone (5 mg twice daily), or no treatment. All patients completed all three of the treatment limbs. MEASUREMENTS: Following each treatment schedule, patients underwent an 11-h cortisol day curve (CDC), and the results were compared with those from the 10 control volunteers on no glucocorticoid treatment. RESULTS: The integrated CDC values were significantly higher in patients taking a full dose of hydrocortisone compared to controls (P < 0.001). There was no significant difference in the integrated CDC between patients on half-dose (P = 0.37) or no hydrocortisone treatment (P = 0.13), compared to control subjects. Peak postabsorption cortisol values were higher in patients receiving full-dose hydrocortisone treatment compared to controls (P < 0.001). There was no significant difference in plasma sodium concentration, blood pressure or corticosteroid-binding globulin between patients on any treatment schedule and controls. CONCLUSION: Adult patients with pituitary disease and partial ACTH deficiency have a cortisol secretory pattern comparable to that of healthy controls. Conventional full-dose replacement with 10 mg twice daily of hydrocortisone produces hypercortisolaemia, whereas half-dose produces a CDC that is not statistically different from that of healthy controls. The results suggest that current conventional glucocorticoid replacement overtreats patients with partial ACTH deficiency under normal unstressed physiological conditions. (What about the rest of the evening/night when cortisol is not being taken? What about people also taking DHEA or thyroid hormones which counteract cortisol? What about those persons living with more stress? There is no substitute for individualization of dosing.--HHL)

Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CG. Tests of adrenal insufficiency. Arch Dis Child. 1999 Apr;80(4):330-3.

AIM: In suspected adrenal insufficiency, the ideal test for assessing the hypothalamo-pituitary-adrenal axis is controversial. Therefore, three tests were compared in patients presenting with symptoms suggestive of adrenal insufficiency. METHOD: Responses to the standard short Synacthen test (SSST), the low dose Synacthen test (LDST), and the 08:00 hour serum cortisol concentration were measured in 32 patients. A normal response to the synacthen test was defined as a peak serum cortisol of >/= 500 nmol/l and/or incremental concentration of >/= 200 nmol/l. The sensitivity and specificity of the 08:00 hour serum cortisol concentration compared with other tests was calculated. RESULTS: Three patients had neither an adequate peak nor increment after the SSST and LDST. All had a serum 08:00 hour cortisol concentration of < 200 nmol/l (7.25mcg/dL). Eight patients had abnormal responses by both criteria to the LDST but had normal responses to the SSST. Three reported amelioration of their symptoms on hydrocortisone replacement. Twenty one patients had a normal response to both tests (of these, 14 achieved adequate peak and increment after both tests and seven did not have an adequate peak after the LDST but had a normal increment). The lowest 08:00 hour serum cortisol concentration above which patients achieved normal responses to both the LDST and SSST was 500 nmol/l. At this cut off value (compared with the LDST), the serum 08:00 hour cortisol concentration had a sensitivity of 100% but specificity was only 33%. CONCLUSION: The LDST revealed mild degrees of adrenal insufficiency not detected by the SSST. The value of a single 08:00 hour serum cortisol concentration is limited.

Ahn RS, Lee YJ, Choi JY, Kwon HB, Chun SI. Salivary cortisol and DHEA levels in the Korean population: age-related differences, diurnal rhythm, and correlations with serum levels. Yonsei Med J. 2007 Jun 30;48(3):379-88.

PURPOSE: The primary objective of this study was to examine the changes of basal cortisol and DHEA levels present in saliva and serum with age, and to determine the correlation coefficients of steroid concentrations between saliva and serum. The secondary objective was to obtain a standard diurnal rhythm of salivary cortisol and DHEA in the Korean population. MATERIALS AND METHODS: For the first objective, saliva and blood samples were collected between 10 and 11 AM from 359 volunteers ranging from 21 to 69 years old (167 men and 192 women). For the second objective, four saliva samples (post-awakening, 11 AM, 4 PM, and bedtime) were collected throughout a day from 78 volunteers (42 women and 36 men) ranging from 20 to 40 years old. Cortisol and DHEA levels were measured using a radioimmunoassay (RIA). RESULTS: The morning cortisol and DHEA levels, and the age- related steroid decline patterns were similar in both genders. Serum cortisol levels significantly decreased around forty years of age (p < 0.001, when compared with people in their 20s), and linear regression analysis with age showed a significant declining pattern (slope=-2.29, t=-4.297, p < 0.001). However, salivary cortisol levels did not change significantly with age, but showed a tendency towards decline (slope=-0.0078, t=-0.389, p=0.697). The relative cortisol ratio of serum to saliva was 3.4-4.5% and the ratio increased with age (slope=0.051, t=3.61, p < 0.001). DHEA levels also declined with age in saliva (slope=-0.007, t=-3.76, p < 0.001) and serum (slope=-0.197 t=-4.88, p < 0.001). In particular, DHEA levels in saliva and serum did not start to significantly decrease until ages in the 40s, but then decreased significantly further at ages in the 50s (p < 0.001, when compared with the 40s age group) and 60s (p < 0.001, when compared with the 50 age group). The relative DHEA ratio of serum to saliva was similar throughout the ages examined (slop=0.0016, t=0.344, p=0.73). On the other hand, cortisol and DHEA levels in saliva reflected well those in serum (r=0.59 and 0.86, respectively, p < 0.001). The highest salivary cortisol levels appeared just after awakening (about two fold higher than the 11 AM level), decreased throughout the day, and reached the lowest levels at bedtime (p < 0.001, when compared with PM cortisol levels). The highest salivary DHEA levels also appeared after awakening (about 1.5 fold higher than the 11 AM level) and decreased by 11 AM (p < 0.001). DHEA levels did not decrease further until bedtime (p=0.11, when compared with PM DHEA levels). CONCLUSION: This study showed that cortisol and DHEA levels change with age and that the negative slope of DHEA was steeper than that of cortisol in saliva and serum. As the cortisol and DHEA levels in saliva reflected those in serum, the measurement of steroid levels in saliva provide a useful and practical tool to evaluate adrenal functions, which are essential for clinical diagnosis.

Ahrens T, Frankhauser P, Lederbogen F, Deuschle M. Effect of single-dose sertraline on the hypothalamus-pituitary-adrenal system, autonomic nervous system, and platelet function. J Clin Psychopharmacol. 2007 Dec;27(6):602-6.

OBJECTIVE: Pharmacological treatment with selective serotonin reuptake inhibitors (SSRIs) is thought to decrease coronary risk in patients with depressive disorder. Selective serotonin reuptake inhibitor intake may (1) attenuate the hypothalamus-pituitary-adrenal (HPA) system, (2) improve disturbances of the autonomous nervous system, and (3) dampen the aggregability of platelets. There is only limited information about the influence of acute treatment with SSRIs on these systems, which is especially important for the initiation of therapy in high-risk cardiac patients. We compared the reaction of these systems to physical stress with single-dose SSRI treatment (100 mg) with that of placebo treatment. METHODS: Using a double-blind, crossover, placebo-controlled design, we assessed HPA system activity via serum cortisol and corticotropin as well as sympathetic nervous system by determining serum norepinephrine and epinephrine levels at baseline and as a response to stress. Analysis of heart rate variability (HRV) provided information on sympathetic/parasympathetic balance. Platelet activity was measured via flow-cytometric determination of platelet surface activation markers along with the serotonin (5-HT) uptake of platelets. RESULTS: We studied 12 healthy young men under placebo and verum conditions. We found higher HPA system activity at baseline and after physical activity under sertraline when compared with placebo, no difference in sympathetic nervous system activity after physical exertion and only slightly heightened baseline epinephrine values after sertraline intake. No difference was seen between sertraline and placebo intake regarding platelet activity and 5-HT uptake, HRV, blood pressure, and HR. CONCLUSIONS: Initiating sertraline treatment increases HPA system activity and epinephrine concentrations. We found no clinically relevant effect of single-dose sertraline treatment on autonomous nervous function, platelet activity, or platelet 5-HT uptake. These findings may not be extrapolated to patients with affective or cardiac disorders or to other SSRIs.

Ahrens T, Deuschle M, Krumm B, van der Pompe G, den Boer JA, Lederbogen F. Pituitary-Adrenal and Sympathetic Nervous System Responses to Stress in Women Remitted From Recurrent Major Depression. Psychosom Med. 2008 May;70(4):461-7.

Objective: To better understand the changes in hypothalamus-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) function after remission of depression. We characterized these systems at baseline and in response to a psychosocial stressor in a cohort of women remitted from recurrent major depression as well as in never-depressed healthy female controls. Methods: Baseline HPA function was measured via saliva cortisol sampling at 8 AM and 4 PM over 7 days as well as quantification of urinary overnight cortisol secretion. The HPA system response to a psychosocial stressor was assessed by measuring serum cortisol and adrenocorticotropic hormone (ACTH) levels and SNS reactivity by determining serum epinephrine (E) and norepinephrine (NE) concentrations as well as autonomic nervous system changes by analysis of heart rate variability (HRV). The stressor included a speech task, mental arithmetic, and a cognitive challenge. Results: In all, we studied 22 women remitted from recurrent major depression (age = 51.0 +/- 1.7 years) and 20 healthy controls (age = 54.2 +/- 1.6 years). Morning saliva cortisol concentrations were lower in remitted patients, paralleled by lower serum cortisol concentrations before stress testing. This group also displayed a blunted cortisol and ACTH response to the stressor, as compared with healthy controls. No between-group differences in HRV parameters were observed. Conclusion: In this group of women remitted from recurrent major depressive disorder, we found evidence of HPA system hypoactivity, both in the basal state and in response to a psychosocial stressor.

Al-Aridi R, Abdelmannan D, Arafah BM. Biochemical Diagnosis of Adrenal Insufficiency: The added Value of Dehydroepiandrosterone Sulfate (DHEA-S) Measurements. Endocr Pract. 2010 Dec 6:1-32.

Objective: The diagnosis of adrenal insufficiency continues to be challenging. This article reviews biochemical tests used in establishing the diagnosis.Methods: A review of relevant literature including our own data on various biochemical tests used to define adrenal function. The advantages and limitations of each approach are discussed.Results: Baseline measurements of serum cortisol are helpful only when they are very low ( ................
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