The clinical utility of alternative, less invasive sampling techniques in the assessment of oral hydrocortisone therapy in children and adolescents with hypopituitarism

OBJECTIVE: The aim of glucocorticoid replacement therapy in ACTH-deficient patients is to mimic the normal diurnal variation of cortisol. However, current hydrocortisone (HC) replacement results in prolonged episodes of hypocortisolaemia and supraphysiological peaks. Plasma cortisol profiles are an accurate yet labour-intensive method of assessing HC replacement. Salivary and bloodspot cortisol sampling methods are less invasive and may be useful tools for assessing glucocorticoid replacement, particularly in children. Therefore, we aimed to define normal salivary and bloodspot cortisol levels in children and their correlations with the gold standard (plasma cortisol). DESIGN: Cross-sectional study in a paediatric teaching hospital. METHODS: Plasma, saliva and bloodspot cortisol profiles were performed on 30 ACTH-deficient children and 22 healthy siblings. RESULTS: In ACTH-deficient patients taking oral HC, the bloodspot-plasma correlation (p=0.90) was stronger than the salivary-plasma correlation (p=0.49). Using target ranges for salivary and bloodspot cortisol levels based on normal data from control subjects, the less invasive sampling methods had low rates of agreement with plasma cortisol target ranges (saliva 65% and bloodspot 75%). Using the plasma-bloodspot correlation regression equation to convert bloodspot to calculated plasma cortisol, there was a high concordance between calculated and actual measured plasma cortisol (88%). CONCLUSION: Bloodspot cortisol sampling is a feasible and accurate method for monitoring oral HC replacement in paediatric patients without necessitating hospital admission, but salivary sampling is not useful.     

Comparison of different regimens of glucocorticoid replacement therapy in patients with hypoadrenalism

Since the optimal glucocorticoid replacement needs to avoid over and under treatment, the adequacy of different daily cortisone acetate (CA) doses was assessed in 34 patients with primary and central hypoadrenalism. The conventional twice CA 37.5 mg/day dose was administered to all patients (A regimen: 25 mg at 07:00 h, 12.5 mg at 15:00 h), while in 2 subgroups of 12 patients the dose was shifted on 2 thrice daily regimens (B: 25 mg at 07:00, 6.25 mg at 12: 00, 6.25 mg at 17:00; C: 12.5 mg, 12.5 mg, 12.5 mg). In other 12 patients the conventional dose was reduced to a thrice 25 mg/day administration (D regimen: 12.5 mg, 6.25 mg, 6.25 mg). In all patients, urinary free cortisol (UFC) excretion and cortisol day curves were evaluated. During the CA 37.5 mg administration, nadir cortisol levels were significantly higher with the thrice daily regimens (143 +/- 31 on B and 151 +/- 34 nmol/l on C) than with the conventional twice (85 +/- 16 nmol/l). Moreover, UFC, morning cortisol levels and mean cortisol day curves were similar in each group. Finally, during D regimen nadir cortisol levels were higher than in A and similar to B and C regimens. No difference in UFC and in cortisol day curves by reducing the CA dose was found. In conclusion, the thrice daily cortisone regimens, in which more physiological cortisol levels are achieved, perform better as replacement therapy. The administration of 25 mg/day CA confirms that replacement therapy is more adequate with a lower dose, particularly in patients with central hypoadrenalism.     

What is the best approach to tailoring hydrocortisone dose to meet patient needs in 2012?

Cortisol is an essential stress hormone and replacement with oral hydrocortisone is lifesaving in patients with adrenal insufficiency. Cortisol has a diurnal rhythm regulated by the central body clock and this rhythm is a metabolic signal for peripheral tissue clocks. Loss of cortisol rhythmicity is associated with fatigue, depression and insulin resistance. A general principle in endocrinology is to replace hormones to replicate physiological concentrations; however, the pharmacokinetics of oral immediate‐release hydrocortisone make it impossible to fully mimic the cortisol rhythm and patients still have an increased morbidity and mortality despite replacement. Traditionally, physicians have replaced hydrocortisone with a total daily dose based on the diurnal 24‐h cortisol production rate with hydrocortisone given twice or thrice daily, with the highest dose first thing in the morning. Monitoring treatment and dose titration has been much debated with some clinicians using cortisol day curves and others relying on clinical symptoms. The main challenge is that there is no established biomarker of cortisol activity. In addressing the clinical question, we have taken the view that an understanding of the cortisol circadian rhythm and hydrocortisone pharmacokinetics is essential when tailoring hydrocortisone dose. Using this approach, we have developed a thrice daily, weight‐related, dosing regimen and a pharmacokinetic and clinical method to monitor treatment. Our argument for replicating the cortisol circadian rhythm is based on the observation that disruption of the rhythm is associated with ill health, and the few studies that have compared different treatment regimens. Further studies are required to definitively test the benefits of replacing the cortisol circadian rhythm in patients with adrenal insufficiency.     

Use of glucocorticoid preparations in congenital adrenocortical dysfunction

Circadian changes in the corticosteroid, testosterone, and ACTH content in the blood plasma were examined to monitor the suppressant effect of glucocorticoids on adrenocortical and hypophyseal functions during administering glucocorticoid drugs to patients with congenital adrenocortical dysfunction. The daily dose of glucocorticoids was given in two intakes according to the two schemes: scheme 1 included the drug intake in the morning and in the afternoon, scheme 2 in the morning and in the evening. The effect of glucocorticoid therapy on the pattern of the circadian rhythm and the absolute corticosteroid and testosterone content was shown to depend on the time of the drug intake. The treatment according to scheme 2 is preferable: the absolute testosterone content was reducing to normal during the whole day. Meanwhile the normal circadian rhythm of the adrenal cortex and hypophysis was preserved.     

Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy

Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50 years. The current standard treatment regimen involves twice‐ or thrice‐daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small‐scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10–15 years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress‐related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over‐ or under‐treatment may result in Cushing‐like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy.     

Doses and steroids to be used in primary and central hypoadrenalism

Traditionally hydrocortisone has been the first choice for replacement therapy in patients with adrenal insufficiency. Paediatricians have used body surface area adjusted dosing and adult physicians have tended to use fixed doses twice or thrice daily. Cortisol secretion has a distinct circadian rhythm being low at the time sleep onset, rising from between 02.00 h and 04.00 h in the morning to peak just after the time of waking then falling during the day. The pharmacokinetics of immediate release hydrocortisone means that no treatment regimen is capable of simulating the normal circadian rhythm of cortisol. Recent data with hydrocortisone infusions suggests that circadian delivery of hydrocortisone can improve biochemical control of patients with adrenal insufficiency. It is anticipated in the future that modified release formulations of hydrocortisone will provide more optimal replacement therapy.     

Why is the management of glucocorticoid deficiency still controversial: a review of the literature

All endocrinologists would like to make glucocorticoid replacement therapy for their hypoadrenal patients as physiological as possible. Many would like the reassurance of a method of monitoring such treatment to confirm that they are achieving this aim. Advances in our knowledge of the normal physiology are relevant to our attempts to do this. The cortisol production rate in normal subjects is lower than was previously believed. The normal pattern of glucocorticoid secretion includes both a diurnal rhythm and a pulsatile ultradian rhythm. Glucocorticoid access to nuclear receptors is 'gated' by the 11-beta-hydroxysteroid dehydrogenase enzymes, which interconvert active cortisol and inactive cortisone. Such complexities make the target of physiological glucocorticoid replacement therapy hard to achieve. The available evidence suggests that conventional treatment of hypoadrenal patients may result in adverse effects on some surrogate markers of disease risk, such as a lower bone mineral density than age-sex matched controls, and increases in postprandial glucose and insulin concentrations. Although the quality of life of hypoadrenal patients may be impaired, there is no evidence of an improvement on higher doses of steroids, although quality of life is better if the hydrocortisone dose is split up, with the highest dose taken in the morning. Thus the evidence suggests that most patients may safely be treated with a low dose of glucocorticoid (e.g. 15 mg hydrocortisone daily) in two or three divided doses, with education about the appropriate action to take in the event of intercurrent illnesses.     

Subcutaneous pulsatile glucocorticoid replacement therapy

The glucocorticoid hormone cortisol is released in pulses resulting in a complex and dynamic ultradian rhythm of plasma cortisol that underlies the classical circadian rhythm. These oscillating levels are also seen at the level of tissues such as the brain and trigger pulses of gene activation and downstream signalling. Different patterns of glucocorticoid presentation (constant vs pulsatile) result not only in different patterns of gene regulation but also in different neuroendocrine and behavioural responses. Current ‘optimal’ glucocorticoid replacement therapy results in smooth hormone blood levels and does not replicate physiological pulsatile cortisol secretion. Validation of a novel portable pulsatile continuous subcutaneous delivery system in healthy volunteers under dexamethasone and metyrapone suppression. Pulsatile subcutaneous hydrocortisone more closely replicates physiological circadian and ultradian rhythmicity.     

Saliva and bloodspot cortisol: novel sampling methods to assess hydrocortisone replacement therapy in hypoadrenal patients

BACKGROUND: In patients with hypoadrenalism, it is often difficult to assess the optimal dose of glucocorticoid replacement. Serial serum cortisol measurements for a cortisol day curve are sometimes used, but this has low acceptability for patients. In this study, we evaluate the reliability of saliva and capillary bloodspot cortisol as alternative methods in assessing cortisol profiles in hypoadrenal patients on hydrocortisone replacement. METHODS: We first examined the correlations between serum cortisol, saliva and bloodspot cortisol in in-hospital patients not on glucocorticoid therapy. We then studied 18 hypoadrenal patients on hydrocortisone therapy and measured their serum, saliva and bloodspot cortisol concurrently at seven different time points in a single day. RESULTS: For in-hospital patients, a significant correlation exists between saliva and serum cortisol (R = 0.7121, P < 0.0001), but there is a stronger correlation between bloodspot and serum cortisol (R = 0.9494, P < 0.0001). The correlations were weaker in hypoadrenal patients on hydrocortisone (saliva and serum cortisol: R = 0.6262, P < 0.001; bloodspot and serum cortisol: R = 0.7871, P < 0.001). When we evaluated each measurement with respect to an arbitrary target range, there was a greater degree of agreement between serum and capillary bloodspot cortisol (85% agreement) than between serum and saliva cortisol (65% agreement) (P < 0.001). CONCLUSION: Bloodspot samplings provide a simple and convenient way for ambulant hypoadrenal patients on hydrocortisone replacement therapy to assess cortisol levels at multiple times in a single day. This may be useful in determining the optimal glucocorticoid dose for hypoadrenal patients.     

Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers

Background All existing long‐term glucocorticoid replacement therapy is suboptimal as the normal nocturnal rise and waking morning peak of serum cortisol is not reproduced. Aim To test whether it is possible to reproduce the normal overnight rise and morning peak in serum cortisol using an oral delayed and sustained release preparation of hydrocortisone (Cortisol_ds). Subjects and methods Six healthy normal male volunteers attended on two occasions, in a single‐dose, open‐label, nonrandomized study. Endogenous cortisol secretion was suppressed by administration of dexamethasone. Cortisol_ds (formulation A or B) was administered at 2200 h on day 1. Blood samples for measurement of cortisol were taken from 2200 h every 30 min until 0700 h, then hourly until 2200 h on day 2. Fifteen body mass index (BMI)‐matched control subjects had serum cortisol levels measured at 20‐min intervals for 24 h. Serum cortisol profiles and pharmacokinetics after Cortisol_ds were compared with those in controls. Results Formulations A and B were associated with delayed drug release (by 2 h and 4 h, respectively), with median peak cortisol concentrations at 4·5 h (0245 h) and 10 h (0800 h), respectively, thereby reproducing the normal early morning rise in serum cortisol. Total cortisol exposure was not different from controls. Conclusions For the first time we have shown that it is possible to mimic the normal circadian rhythm of circulating cortisol with an oral modified‐release formulation of hydrocortisone, providing the basis for development of physiological circadian replacement therapy in patients with adrenal insufficiency.     

Glucocorticoid replacement therapy: are patients over treated and does it matter?

BACKGROUND AND OBJECTIVES Adequate assessment of patients on glucocorticoid replacement therapy is of great importance to avoid the consequences of under or over treatment, but no simple test is available for this. The aims of this study were (1) to assess adequacy of glucocorticoid replacement in hypoadrenal patients, (2) to correlate serum cortisol levels (cortisol day curve) with 24-hour urine free cortisol excretion and (3) to assess the impact of glucocorticoid dose optimization on markers of bone formation and bone resorption. DESIGN Cross-sectional study of current replacement therapy and a prospective study of the effect of dose alteration on bone turnover markers. PATIENTS Thirty-two consecutive patients on replacement glucocorticoid therapy (12 Addison’s disease, 20 hypopituitarism) from a University teaching hospital out-patient department. MEASUREMENTS Serum and urinary cortisol, osteocalcin, N-telopeptide of type I collagen (NTX) and bone mineral density. RESULTS 28/32 (88%) patients required a change of therapy; 24/32 (75%) a total reduction in dose, 18/32 (56%) a change in replacement therapy regimen or drug and 14/32 (44%) both changes. The mean daily dose of hydrocortisone was reduced from 29.5 ± 1.2 to 20.8 ± 1.0 mg. A significant correlation was found between peak cortisol and 24-hour urine free cortisol/creatinine (Spearman correlation r = 0.60, P < 0.0001; n = 51). Following hydrocortisone dose reduction, median osteocalcin increased from 16.7 μg/l (range 8.2–65.7) to 19.9 μg/l (8.2–56.3); P < 0.01, with no change in the NTX/creatinine ratio. CONCLUSIONS A high proportion of patients on conventional corticosteroid replacement therapy are over treated or on inappropriate replacement regimens. To reduce the long term risk of osteoporosis, corticosteroid replacement therapy should be individually assessed and over replacement avoided.     

The emergence of salivary cortisol circadian rhythm and its relationship to sleep activity in preterm infants

OBJECTIVE: The circadian rhythm of cortisol is established at between 8 and 12 postnatal weeks in term infants. However, there is limited information about the effect of prematurity on this rhythm. We evaluated the emergence of the salivary cortisol circadian rhythm in premature infants and its relationship to the onset of sleep daily rhythm. DESIGN AND PATIENTS: A longitudinal study of a group of nine premature infants (gestational age 31-34 weeks) was performed. Salivary samples were obtained in the morning and at night at 2, 4, 8, 12, 16, 20 and 24 postnatal weeks and the babies' sleeping periods were recorded by their mothers. MEASUREMENTS: Cortisol was determined by RIA in 25-microl salivary samples. Two techniques based on assay coefficients of variation were used to characterize the circadian pattern of cortisol. RESULTS: Five infants (55%) established and maintained their cortisol rhythm at 2 and 8 postnatal weeks. In the remaining four infants the age of appearance was 12 and 16 weeks. This rhythm emerged in the group as a whole between 8 and 12 postnatal weeks. The circadian rhythm of sleep was detected starting from the eighth postnatal week. CONCLUSIONS: Our data suggest that in this group of premature infants the circadian maturation of the hypothalamic-pituitary-adrenal axis occurred at the same postnatal age as reported for term infants and that there was a parallelism between the appearance of such rhythm and the onset of sleep rhythm.     

Criteria of cure and remission in Cushing's disease: an update

We review the clinical and biochemical criteria used for evaluation of the transsphenoidal pituitary surgery results in the treatment of Cushing's disease (CD). Firstly, we discuss the pathophysiology of the hypothalamic-pituitary-adrenal axis in normal subjects and patients with CD. Considering the series published in the last 25 years, we observed a significant variation in the remission or cure criteria, including the choice of biochemical tests, timing, threshold values to define remission, and the interference of glucocorticoid replacement or previous treatment. In this context we emphasize serum cortisol levels obtained early (from hours to 12 days) in the postoperative period without any glucocorticoid replacement or treatment. Our experience demonstrates that: (i) early cortisol < 5 to 7 microg/dl, (ii) a period of glucocorticoid dependence > 6 mo, (iii) absence of response of cortisol/ACTH to CRH or DDAVP, (iv) return of dexamethasone suppression, and circadian rhythm of cortisol are appropriate indices of remission of CD. In patients with undetectable cortisol levels early after surgery, recurrence seems to be low. Finally, although certain biochemical patterns are more suggestive of remission or surgical failure, none has been proven to be completely accurate, with recurrence observed in approximately 10 to 15% of the patients in long-term follow-up. We recommended that patients with CD should have long-term monitoring of the CRH-ACTH-cortisol axis and associated co-morbidities, especially hypopituitarism, diabetes mellitus, hypertension, cardiovascular disturbances, and osteoporosis.     

Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency

BACKGROUND: Glucocorticoid therapy is associated with potentially serious side-effects, but there is no information available regarding glucocorticoid requirement in adult hypopituitary patients with partial ACTH deficiency. SUBJECTS: Ten male adult hypopituitary patients with partial ACTH deficiency, baseline plasma 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.     

Longitudinal evaluation of the development of salivary cortisol circadian rhythm in infancy

OBJECTIVE  Although an outstanding characteristic of the adrenocortical function of children and adults is its circadian rhythm, little information is available about the age of appearance of such rhythm in infancy. The main obstacle has been the ethical difficulty in obtaining serial blood samples from healthy infants. We monitored the development of cortisol daily rhythm using non-invasive salivary cortisol determination.
DESIGN AND PATIENTS  A longitudinal study of a group of 9 healthy infants was performed. Salivary samples were obtained in the morning, afternoon and night at 2, 4, 8, 12, 16, 20 and 24 post-natal weeks from all infants.
MEASUREMENTS  Cortisol was determined by RIA in 25-μl salivary samples. Two techniques based on assay coefficients of variation were employed to characterize a normal circadian pattern of cortisol.
RESULTS  Five infants (55%) established and maintained their cortisol rhythm as early as at 2, 4 and 8 weeks of age. In the remaining 4 infants the age of appearance was 12 and 20 weeks. This rhythm emerged in the group as a whole at a mean age of 8 weeks.
CONCLUSIONS  Our data suggest that, in most normal infants, the development of hypothalamic–pituitary–adrenal axis circadian maturation may occur at a much earlier age than previously described.     

Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements

OBJECTIVE: Evaluation of glucocorticoid replacement quality in adrenal insufficiency (AI) relies primarily on clinical judgement and thus largely depends on the physician's expertise. It is a matter of debate whether cortisol day curves are of value in assessing glucocorticoid replacement quality. Here we compared the results of a structured clinical assessment to the outcome of repeated, timed serum cortisol measurements. DESIGN: Cross-sectional study in the outpatient department of a university teaching hospital. PATIENTS: Forty-six patients (19 men, 27 women, age range 16-76 years) with primary (n = 23) and secondary (n = 23) AI on stable replacement with a median dose of 37.5 mg cortisone acetate (range 25-50 mg) since 10 +/- 7 years (range 1-31 years). MEASUREMENTS: Clinical performance was scored by structured assessment of signs and symptoms, physical examination and routine biochemical tests. Serum cortisol was measured on two to three separate occasions in three timed samples after the morning glucocorticoid dose. Bone mineral density was measured in 15 patients with long-standing glucocorticoid replacement. RESULTS: Thirty-seven patients were considered well replaced, whereas clinical scores suggested over- or under-replacement in five and four, respectively. There was no correlation of the clinical score with total or body weight-adjusted glucocorticoid dose. The mean z score of serum cortisol differed significantly between under- and over-replaced patients (P < 0.05) but neither group differed significantly from well-replaced patients. Bone mineral density was normal in all patients studied. CONCLUSIONS: Our results suggest that serum cortisol day curves are of limited value in the monitoring of glucocorticoid replacement. Bone mineral density in AI is generally normal and does not require routine follow-up.     

Circadian rhythm of plasma testosterone in men with idiopathic hypogonadotrophic hypogonadism before and during pulsatile administration of gonadotrophin-releasing hormone

OBJECTIVE: The aim was to investigate whether a pulsatile discharge of LH from the pituitary is necessary to achieve the circadian secretion of testosterone. DESIGN: The daily rhythm of the androgen has been studied in patients with idiopathic hypogonadotrophic hypogonadism (IHH) both in the absence of therapy and during pulsatile administration of gonadotrophin releasing hormone (GnRH). PATIENTS: Six patients with IHH and ten normal subjects were analysed. Blood sampling was performed at 2-hourly intervals, for 24 hours. The IHH patients then received synthetic GnRH i.v. at the rate of one pulse every 2 hours (10 micrograms/pulse). On day 11 of treatment, blood samples were taken for the rhythm analysis every 2 hours, for 24 hours. MEASUREMENTS: Plasma testosterone and LH were measured in the individual samples by radioimmunoassay. Evaluation of the rhythm was performed by cosinor analysis. RESULTS: A significant circadian rhythm of plasma testosterone was statistically validated in the normal subjects, whereas no rhythm was detected in the IHH patients in the absence of therapy. On day 11 of GnRH pulsatile administration the IHH patients showed normal testosterone levels and a statistically significant circadian rhythm of the androgen was evident, with acrophase between 0700 and 0800 h. Moreover, the amplitude, acrophase and mesor of testosterone rhythm in IHH patients in the course of treatment were statistically indistinguishable from the corresponding values in the normal subjects. Plasma LH did not show statistically significant circadian variations, either in the control group or in the IHH patients before or during therapy. CONCLUSIONS: We conclude that a physiological circadian rhythm of plasma testosterone can be obtained, in IHH men, by treatment with GnRH. Since the pulsatile administration of exogenous GnRH at constant doses induced a circadian rhythm in testosterone and no daily variations in LH were evident, we suggest that, although a pulsatile secretion of LH is probably necessary for the synchronization of the circadian rhythm with acrophase in the morning, the testosterone variations might be the results of a local testicular modulation of LH action.     

Corticoids secretion in primary aldosteronism. I. Diurnal variation and the effect of dexamethasone (author's transl)

For the purpose of studying the metabolism of adrenocortical steroids in primary aldosteronism, diurnal variation and the effect of dexamethasone were examined in four patients. The circadian rhythm of cortisol was observed in plasma aldosterone and corticosterone in all cases in the preoperative state. With regards to plasma progesterone, 17 alpha-hydroxyprogesterone and dehydroepiandrosterone-sulfate, however, no demonstrable change was noted. Dexamethasone was administered to two subjects for 10 days before the operation. As a result, the urinary aldosterone of one subject decreased on the 5th day after the administration but was restored to its original value on the 10th day, while the urinary aldosterone of the other subject did not decrease at all. On the first day after the operation, the value of plasma cortisol was elevated, losing its circadian rhythm. On the 7th day after the operation, the normal circadian rhythm was observed again in plasma cortisol. Plasma aldosterone was reduced to the normal range without any demonstrable changes on the first and 7th days after the operation. On the 30th day after the operation, a slight cortisol-like circadian rhythm was observed. Plasma levels of progesterone, corticosterone, 17 alpha-hydroxyprogesterone and dehydroepiandrosterone-sulfate were almost within the normal range throughout the pre- and post-operative periods. Although plasma progesterone was within the normal range, it tended to be lower in the postoperative state than in the preoperative state.     

Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasia

OBJECTIVE: Conventional hydrocortisone therapy in adrenal insufficiency cannot provide physiological replacement. We have explored the potential of circadian delivery of hydrocortisone as proof of concept for such therapy delivered in modified-release tablet formulation. METHODS: We investigated whether the circadian intravenous infusion of hydrocortisone could improve control of ACTH and androgen levels. Two healthy subjects, two patients with Addison's disease and two patients with congenital adrenal hyperplasia (CAH) were studied. RESULTS: In patients on thrice daily oral hydrocortisone, peak serum cortisol levels were higher than in normal subjects and overnight levels were very low. Patients had very high plasma ACTH levels before their morning dose of hydrocortisone, both at the beginning and at the end of their conventional oral therapy: mean +/- SEM 311.8 +/- 123.2 and 311.2 +/- 85.4 ng/l, respectively. In the patients with CAH, serum 17-hydroxyprogesterone levels were also elevated: 550 and 642 nmol/l at the beginning and 550 and 777 nmol/l at the end of conventional treatment, respectively. The overall 24-h mean cortisol levels were similar for conventional oral hydrocortisone and the circadian infusion. At 0700 h, ACTH levels were much higher on conventional treatment than after circadian infusion: mean +/- SEM 311.2 +/- 85.4 vs. 70.5 +/- 45.0 ng/l, respectively (P < 0.05). The same pattern was observed in 17-hydroxyprogesterone levels, which were 550 and 777 nmol/l after conventional treatment and 3 and 64 nmol/l after circadian infusion. CONCLUSIONS: In patients with poor biochemical control of Addison's disease and CAH, a 24-h circadian infusion of hydrocortisone can decrease morning ACTH and 17-hydroxyprogesterone levels to near normal.