Hypothalamo-pituitary-adrenal Suppression Research Articles

Characterising approaches to steroid therapy in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2.

We describe approaches to steroid therapy use in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and examine the association between steroid therapy and key clinical markers of severity. We conducted a retrospective review of children (<18 years) admitted to a tertiary paediatric hospital in the UK with PIMS-TS. We collected data on if and why steroid therapy was used; the duration, type and dosing of steroids prescribed; and approaches to hypothalamo-pituitary-adrenal (HPA) axis monitoring, if performed. We examined associations between steroid exposure/total steroid dose (mg/m2 /day) and paediatric intensive care unit admission, mechanical ventilation and inotropic support. Steroid therapy was commenced in most children (84.9%, n = 104) with a median total daily steroid dose (hydrocortisone equivalent) of 271.0 mg/m2 /day (interquartile range 232.5-355.5) and treatment length of 26.0 days (interquartile range 19.0-32.0). Dosing regimens predominantly involved a short course of high-dose methylprednisolone followed by tapering oral prednisolone. Basal and/or dynamic testing of the HPA axis was conducted in a minority (11.8%, n = 15) and was normal. Duration of steroid therapy correlated positively with durations of paediatric intensive care unit admission (r = 0.407, P < 0.001) and mechanical ventilation (r = 0.797, P < 0.001). A greater proportion of children receiving steroid therapy also received inotropic support compared to those that did not receive steroid therapy (71.4% vs. 45.5%, P = 0.025). Prolonged, high-dose steroid therapy is often used in the management of severe PIMS-TS with the potential for HPA axis suppression and should be withdrawn carefully.

Topical corticosteroids in plaque psoriasis: a systematic review of risk of adrenal axis suppression and skin atrophy

Topical steroids have been used for more than 50 years in mild-to-moderate plaque psoriasis and carry a theoretical risk of adverse events. The aim of this systematic literature review was to evaluate the risk of hypothalamo-pituitary-adrenal (HPA) axis suppression and the risk of skin atrophy with topical steroids in the treatment of plaque psoriasis. A systematic search between 1980 and January 2011 in Medline, Embase and Cochrane databases (English, French language, adults), using the keywords 'psoriasis'/exp/mj AND 'corticosteroid'/exp/mj, Altogether 1269 references were found. Of these 1124 articles were excluded by reading the abstract and 123 by reading the article. A total of 22 randomized trials were selected. Effects on HPA axis: Thirteen studies, with a sample size varying from 7 to 341 patients, were selected. The effect on HPA axis was evaluated by the morning cortisol level (11 studies), the 24 h urine steroid levels (five studies) and/or by the Synacthen test (three studies). Reduction of morning cortisol was observed in 0-25% of patients in 10 short-term studies (two in scalp psoriasis, eight in body psoriasis) and in 48% of patients in the remaining short-term study (body psoriasis). Only four of these studies with three on body psoriasis evaluated the effect of long-term treatment defined as 6-month treatment duration or longer and did not identify HPA axis suppression by cortisol level measurement. The Synacthen test, considered as the gold standard to assess HPA axis, was always normal. There was no evidence of clinically significant HPA axis suppression due to absorption of topical steroids even when treating the scalp or in patients with extensive disease. Risk of skin atrophy: Thirteen studies with topical steroid evaluating treatment durations from 4 weeks to 1 year were analysed. The frequency of skin atrophy assessed clinically, varied from 0% to 5% of patients. The literature analysis on topical steroids in psoriasis is reassuring although the quality of safety studies is limited with a majority of short-term studies. Although short-term biological effects of topical steroids on the HPA axis were observed in several clinical studies, they were not associated with clinical signs. Adequately designed long-term studies would be necessary to better determine the risk of skin atrophy using modern methods of evaluation such as dermoscopy and echography.

Delayed recovery of hypothalamo-pituitary-adrenal axis

Sir, We report a case of secondary adrenal insufficiency (AI), who had delayed recovery of hypothalamo-pituitary-adrenal (HPA) axis after 18 months. This case highlights regular follow-up of such cases till recovery to avoid acute adrenal crisis during stress. A 38-year-old male presented initially around 21 months back with history of fever, headache, and hemoptysis of 2-week duration. Despite antibiotics, symptoms continued and he was transferred to our center. He reported to have taken alternative forms of medication in 2000, 2003, and December 2008. He also reported to have violaceous striae over his abdomen, thighs, and axillae for last 5 years. At the same time, he also noticed weight gain around abdomen, upper torso, and mooning of face. He was operated for bilateral posterior subcapsular cataract three years back. He also had easy bruisability and proximal muscle weakness. Examination revealed cushingoid habitus and postural hypotension with low venous plasma glucose (62-72 mg/dl), serum Na - 129 meq/l, K - 5.0 meq/l, basal (8 000 h) cortisol - 1.97 μg/dl, cortisol (1 600 h) - 1.13 μg/dl, and adrenocorticotropic hormone (ACTH)-stimulated cortisol - 8.29 μg/dl, suggesting a suppressed HPA axis. His chest X-ray was normal. Subnormal cortisol in presence of cushingoid habitus strongly suggested AI secondary to exogenous corticosteroid ingestion. He was started on suboptimal dose of hydrocortisone replacement with marked recovery of symptoms and educated about AI symptoms. Gradually, his hydrocortisone replacement was withdrawn over three months and he was educated about self management during period of stress. He was issued a steroid dependency card and planned for regular follow-up. He was followed up quarterly and his HPA axis was evaluated with ACTH stimulation test [Table 1]. His HPA axis recovered after 18 months. Table 1 Basal and adrenocorticotropic hormone stimulated cortisol level Glucocorticoids (GCs) were first used in 1948 for management of rheumatoid arthritis with marked benefit; however, thereafter multiple side effects of this drug have been reported in literature. One major and life-threatening side effect is development of secondary AI. Most common cause of AI in clinical practice is exposure to exogenous steroids. Administration of exogenous corticosteroids leads to suppression of the HPA axis by decreasing CRH synthesis and secretion and by blocking the trophic and ACTH-releasing actions of CRH on the anterior pituitary. This leads to atrophy of the corticotrophs in anterior pituitary. As a result, in the absence of ACTH, the adrenal cortex loses the ability to produce cortisol.[1] This development of secondary AI is not fully dependant on dose, duration, route of corticosteroid exposure and there is considerable inter individual variation. Most authors believe that more than 3 weeks of exposure to supraphysiologic GCs is sufficient for HPA axis suppression, whereas if doses are high, HPA axis may get suppressed very quickly.[2] It is widely reported in literature that following exposure to exogenous GCs, recovery of HPA axis requires 6 to 12 months.[2] However, in our case, it took 18 months of steroid-free period to recover his HPA axis as assessed by synacthen test. It is not possible physiologically to specify a period for recovery of HPA axis when there is so much of inter individual differences in response to GCs on exposure. Thus, we propose that patients after prolonged exposure to exogenous steroids should be vigilantly followed up for development of AI after GC withdrawal and subsequently observed for a sufficiently long duration for assessment of recovery of HPA axis.

Corticosteroid physiology and principles of therapy

The adrenal cortex secretes glucocorticoids (GC), mineralocorticoids (MC) and androgens. GC maintain homeostasis, MC regulate fluid and electrolyte balance and adrenal androgens contribute to development of secondary sexual characteristics. Pharmacologic GC therapy is frequently indicated in the pediatric age group. Besides having many important side effects, prolonged high dose systemic GC therapy has a suppressive effect on endogenous steroid production. Therefore, GC therapy should be withdrawn gradually and stopped based on assessment of hypothalamo-pituitary-adrenal (HPA) axis recovery. Patients with HPA axis suppression require physiological replacement of GC along with enhancement of doses during periods of stress. Due to its immunosuppressive effects, issues about safety and efficacy of live virus vaccines in patients receiving systemic high dose GC therapy must be borne in mind.

Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures.

Glucocorticoid withdrawal, depending on the dose and duration of treatment, results in a transient but sometimes prolonged reduction in hypothalamo-pituitary-adrenal (HPA) axis secretory responsiveness. As the anatomic basis of HPA axis suppression remains uncertain, we have directly examined changes in trophic activity within the rat anterior pituitary gland following dexamethasone withdrawal and re-treatment. Treatment of adrenalectomised, male Wistar rats with dexamethasone results in a discrete, highly significant burst of apoptosis in the anterior pituitary with concurrent suppression of mitosis. Despite a surge in mitotic activity immediately after dexamethasone withdrawal, calculated total anterior pituitary cell populations remain below that seen in untreated adrenalectomised controls. Repeated exposures to dexamethasone show that the dexamethasone-sensitive cell population that is deleted by apoptosis is partially but not completely restored. As the amplitude of apoptotic bursts induced by second and third dexamethasone exposures are similar but smaller than that induced by initial exposure, it appears that the very first exposure to dexamethasone deletes a subset of anterior pituitary cells that are either not restored at all, or are only replaced very slowly. The reduced proportion of corticotrophs contributing to the increase in mitotic index after dexamethasone withdrawal corroborates this. Although continued cell turnover within the pituitary predicts that the absolute cellular deficit would diminish with time, the effects seen may contribute to the delayed recovery of pituitary axis function following cessation of glucocorticoid treatment.

What time of day do patients take steroid tablets?

Expert advice is that those taking systemic corticosteroidsshould take the tablets in the morning to reduce the risk ofsuppression of the hypothalamo-pituitary–adrenal (HPA)axis (1,2). Systemic steroid administration in the evening ismore likely to cause clinically significant HPA suppression(3). For some years printed advice to patients attending thischest clinic under the care of one of the consultants hasadvised the morning use of tablets, but we decided to surveyhow patients attending this chest clinic and a rheumatologyclinic in the same hospital actually used their tablets.

Partially autonomous cortisol secretion by incidentally discovered adrenal adenomas

Recent studies of the function of adrenal “incidentalomas” have revealed that a proportion of those tumors secrete cortisol insufficiently to produce overt clinical Cushing s syndrome, but that their autonomous cortisol production can suppress the hypothalamo-pituitaryadrenal (HPA) axis to various degrees; this needs to be recognized to avoid acute adrenal insufficiency after adrenalectomy. Several diagnostic approaches have been utilized to identify the partially autonomous cortisol-secreting adenomas. It has been suggested that a lack of normal suppression of cortisol (> 140 nmol/L) on the morning after 1-mg oral dexamethasone at bedtime would identify most functional autonomous cortisol-secreting tumors. Based on this criterion, approximately 18% of published cases of incidentalomas would secrete cortisol autonomously. However, other tests indicating alterations of the HPA axis, such as abnormal adrenal iodocholesterol uptake or decreased plasma levels of dehydroepiandrosterone sulfate (DHAS), were found to be present in up to 79%–86% of incidentalomas. This is illustrated by the description of three patients with incidentalomas with plasma cortisol levels < 140 nmol/L in 2 of 3 patients after 1-mg dexamethasone overnight; however, various degrees of HPA axis suppression were demonstrated by an i.v. dexamethasone (4-mg) suppression test, decreased plasma DHAS levels and unilateral adrenal iodocholesterol uptake. After laparoscopic adrenalectomy, the response of plasma cortisol to 250 μg i.v. of ACTH (1–24) was subnormal in 2 of 3 patients and was restored to normal within 2 months. We conclude that the criterion of a plasma cortisol level > 140 nmol/L, after an overnight 1-mg dexamethasone suppression test, underestimates the incidence of partially autonomous cortisol-secreting adrenal adenomas. The literature on this subject is reviewed, and recommendations for evaluation and treatment are presented.

HYPOTHALAMO‐PITUITARY‐ADRENAL AXIS SUPPRESSION IN ASTHMATIC ADULTS TAKING HIGH DOSE BECLOMETHASONE DIPROPIONATE

SUMMARYInhaled corticosteroids control symptoms of chronic asthma in most patients. Use of drugs such as beclomethasone dipropionate (BDP) and budesonide is being encouraged as the importance of airways inflammation in asthma is increasingly appreciated. Beclomethasone dipropionate is used in doses of up to 2000 μg daily (equivalent to eight puffs of Beclorforte inhaler) and the Data Sheet warns that systemic absorption sufficient to cause suppression of the hypothalamo‐pituitary‐adrenal (HPA) axis may occur in some patients taking 2000 μg. HPA suppression to an extent which is clinically relevant has not been reported in asthmatic adults taking lower doses of BDP. We report six cases of HPA hypofunction occurring in patients on long‐term treatment with BDP, in a dose of 1500 μg daily. Patients taking BDP in a dose of 1500 μg daily might be at risk of adrenal crisis and should carry steroid cards unless HPA function has been assessed and found normal.

Screening for hypothalamo-pituitary-adrenal axis suppression in asthmatics taking high dose inhaled corticosteroids

High dose inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis. Several tests are available to screen for this suppression but it is not clear which is the most useful. HPA function was assessed in 78 adult asthmatics inhaling long-term, high dose (median 1600 micrograms; range 1200-2650 micrograms) beclomethasone dipropionate (n = 69) or budesonide (n = 9). Screening tests performed in all patients were 9 am serum cortisol, short tetracosactrin test and 24-h urine free cortisol excretion. Eleven patients also underwent insulin stress tests. Subnormal results were: 9 am cortisol less than 190 nmol l-1; urine free cortisol less than 80 nmol 24 h-1; rise in cortisol in response to tetracosactrin or hypoglycaemia less than 200 nmol l-1 and/or achieved cortisol less than 500 nmol l-1. HPA suppression (defined as subnormal results of at least two of the three initial tests and/or subnormal response to hypoglycaemia), was found in 16 patients. In the 11 patients who underwent insulin stress tests, results of all initial tests were normal in three, one test was abnormal in three and two tests were abnormal in four patients. All three tests were abnormal in the remaining patient. The response to hypoglycaemia was normal in the three patients whose screening tests were all normal; HPA suppression was present in seven patients and one patient had a borderline result. Close correlation was observed between the maximum cortisol during hypoglycaemia and both urine free cortisol (rs = 0.84; P = 0.001) and post-tetracosactrin cortisol (r = 0.75; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrine regulation in depression. II. Discrimination of depressed from nondepressed patients.

Forty-two patients with endogenomorphic depression (ED) and 42 patients with other psychiatric disorders received an overnight dexamethasone test of hypothalamopituitary-adrenal (HPA) suppressibility. Plasma and urinary cortisol measures showed that the ED patients had significantly greater HPA activity before dexamethasone and less complete HPA suppression after dexamethasone. High cortisol vlaues after dexamethasone correlated strongly with spontaneous HPA disinhibition, as indicated by high baseline midnight plasma cortisol levels. Criteria for defining normal suppression responses were developed. All patients with depressive neuroses and most patients with other nondepressive disorders had completely normal responses to dexamethasone. About half of the ED patients had abnormal responses, whether or not they were receiving other drugs at the time of the test. Drug-free patients with depressive neuroses or other disorders showed no abnormal responses to dexamethasone. The effects of psychotropic drugs on the test require further study. Patients with two or more abnormal cortisol values after administration of dexamethasone were identified correctly as ED at confidence levels close to 100%. The dexamethasone suppression test may be of value as a laboratory aid in the diagnosis of "endogenous" depression.

Neuroendocrine Regulation in Depression

The regulation of hypothalamopituitary-adrenal (HPA) function in depressed patients was studied by a midnight dexamethasone suppression test. By using an observation period of 24 hours postadministration of dexamethasone, a graded series of abnormal test responses was identified. Depressed patients show abnormal early escape from suppression rather than absolute resistance to HPA suppression by dexamethasone. With increasing severity of depression, this escape occurs progressively more early on the day after administration of dexamethasone. These abnormalities were strongly related to the presence of HPA hyperactivity before dexamethasone was given. The essential disturbance of neuroendocrine regulation in depression is a failure of the normal brain inhibitory influence on the HPA system. This disinhibition of HPA activity suggests that there is an abnormal limbic system drive on the HPA axis in primary depressive illness.

Neuroendocrine Identification of Depressed Patients

Recent studies of hypothalamo--pituitary--adrenal (HPA) suppression in depressed patients indicate that these subjects often show abnormal early escape of plasma cortisol levels following an initial suppression. Non-depressed psychiatric inpatients usually show normal sustained HPA suppression. The responses of 49 depressed and 30 non-depressed patients have been analysed to develop criteria which can make the dexamethasone suppression test suitable for outpatient studies. The cortisol levels measured in a 24-hour urine collection and a single blood sample post-dexamethasone were sufficient to enable 61% of the depressed patients to be identified correctly at a confidence level of 90%, on the basis of at least one abnormal cortisol value. When both cortisol values were abnormal 35% of the depressed patient were identified correctly at a confidence level of 100%. Patients with "endogenous" depressive profiles had the most abnormal results. A normal response to this test will not necessarily exclude the diagnosis of primary depressive illness. An abnormal response to the test may be of help in confirming the diagnosis. With the simplified procedure outpatient studies may become possible.

Single daily dose corticosteroid treatment.

Thirteen patients with rheumatoid or psoriatic arthritis who had not previously received corticosteroids were treated with prednisolone in a single-dose each morning. Insulin-hypoglycaemia tests were performed before starting steroids in each patient, and again at the conclusion of the study in twelve of the thirteen (duration of steroid treatment 8-40 m). There was no difference in the mean basal or peak levels of corticosteroids, or the mean peak of growth hormone (GH) in the tests done before or during treatment, although one patient lost GH responsiveness. There was thus no evidence of hypothalamo-pituitary-adrenal (HPA) suppression in any of the twelve patients, and there was a good therapeutic response in twelve out of thirteen. One patient was dropped from the trial because treatment failed. In contrast, of seven patients who had received a similar total dose of prednisolone twice daily, three showed HPA suppression and two had lost GH responsiveness.

Recovery of hypothalamo‐pituitary‐adrenal function in the rat after prolonged treatment with betamethasone

1. Betamethasone caused growth retardation, adrenal atrophy and impaired hypothalamo-pituitary-adrenal (HPA) activity in the rat.2. In spite of the profound impairment, recovery of normal HPA function was rapid, but the growth retardation persisted.3. The ability of the pituitary gland to secrete basal corticotrophin (ACTH), recovered more rapidly and the adrenocorticotrophic response to stress less rapidly than the ability of the adrenal cortex to respond to ACTH.4. The degree of HPA suppression was not determined by the total dose of steroid.5. The possible significance of the results is discussed.