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Comparison of mean serum cortisol levels in patients with Addison's disease and congenital adrenal hyperplasia (CAH) during conventional oral replacement therapy and during circadian i.v. infusion of hydrocortisone (adapted from Clinical Endocrinology 2006 65: 45–50 (16)).
Source publication
Patients with adrenal insufficiency need lifelong glucocorticoid replacement, but many suffer from poor quality of life, and overall there is increased mortality. Moreover, it appears that use of glucocorticoids at the higher end of the replacement dose range is associated with increased risk for cardiovascular and metabolic bone disease. These dat...
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Citations
... Another relevant factor, additionally contributing to the increased incidence of metabolic diseases in patients with hypopituitarism is a prolonged over-replacement with hydrocortisone in those individuals with a diagnosis of secondary AI [31]. Indeed, over-replacement is unfortunately quite common [32] and can lead to a significant proinflammatory state with weakened immune defense [33], which in turn increases the risk of infection and recurrent hospitalizations [4]. While GHD is usually not substituted during hospitalization for acute medical conditions, as previous evidence suggests an increased mortality associated with substitution during acute medical conditions [34], inadequate replacement therapy of secondary AI is a leading cause of in-hospital morbidity and mortality among patients with hypopituitarism and its adequate acute management still remains a major challenge [35]. ...
Hypopituitarism is a highly heterogeneous multisystem disorder that can have a major impact on long-term morbidity and mortality, but even more so during acute medical conditions requiring hospitalization. Recent studies suggest a significant in-hospital burden with prolonged length of stay, increased rate of intensive care unit (ICU) admission, and initiation of mechanical ventilation − all of which may lead to an increased risk of in-hospital mortality. On the one hand, patients with hypopituitarism are often burdened by metabolic complications, including obesity, hypertension, dyslipidemia, and hyperglycemia, which alone, or in combination, are known to significantly alter relevant physiological mechanisms, including metabolism, innate and adaptive immune responses, coagulation, and wound healing, thereby contributing to adverse in-hospital outcomes. On the other hand, depending on the extent and the number of pituitary hormone deficiencies, early recognition of hormone deficiencies and appropriate management and replacement strategy within a well-organized multidisciplinary team are even stronger determinants of short-term outcomes during acute hospitalization in this vulnerable patient population. This review aims to provide an up-to-date summary of recent advances in pathophysiologic understanding, clinical implications, and recommendations for optimized multidisciplinary management of hospitalized patients with hypopituitarism.
... Two studies [33,34] examined the relationship between glucocorticoid replacement dose and mortality, and in both cases a significant association between higher doses and an increased risk of death was observed. This is in line with findings in other contexts [36,37,41], in which higher glucocorticoid replacement doses were associated with an adverse cardiometabolic profile, and with a consequent increase in morbidity and mortality. Nevertheless, it should be noted that this association does not necessarily imply a causal relationship, as the available evidence is observational in nature Based on the available evidence, a slight mortality excess also in NFPA patients with apparently preserved pituitary function cannot be excluded. ...
Background
Patients with non-functioning pituitary adenoma (NFPA) often present with a variety of clinical manifestations and comorbidities, mainly determined by the local mass effect of the tumor and by hypopituitarism. Whether this has an impact on overall mortality, however, is still unclear.
Methods
PubMed/Medline, EMBASE, and Cochrane Library databases were systematically searched until May 2023 for studies reporting data either about standardized mortality ratios (SMRs) or about predictors of mortality in patients with NFPA. Effect sizes were pooled through a random-effect model. This systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO, #CRD42023417782).
Results
Eleven studies were eligible for inclusion in the systematic review; among these, five studies reported data on SMRs, with a total follow-up time of approximately 130,000 person-years. Patients with NFPA showed an increased mortality risk compared to the general population (SMR = 1.57 [95%CI: 1.20–1.99], p < 0.01). Age and sex appeared to act as effect modifiers, with a trend towards higher SMRs in females (SMR = 1.57 [95%CI: 0.91–2.41], p = 0.10) than in males (SMR = 1.00 [95%CI: 0.89–1.11], p = 0.97), and in patients diagnosed at age 40 years or younger (SMR = 3.19 [95%CI: 2.50–3.97], p < 0.01) compared to those with later onset of the disease (SMR = 1.26 [95%CI: 0.93–1.65], p = 0.13). The trend towards excess mortality was similar in patients with normal (SMR = 1.22 [95%CI: 0.94–1.53], p = 0.13) or deficient (SMR = 1.26 [95%CI: 0.82–1.79], p = 0.27) pituitary function.
Conclusions
Excess mortality is observed in patients with NFPA, regardless of pituitary function, especially in women and in patients with a younger age at diagnosis.
... [10][11][12] This notion has been challenged by studies aiming to assess their health-related quality of life (QoL). [13][14][15][16][17][18] The reasons for incomplete recovery of well-being with current replacement regimens are not well understood. The cause of adrenal insufficiency (Table 2) may be partly responsible for the differences in QoL during stable chronic treatment with either glucocorticoid alone or supplemented with fludrocortisone. ...
... 19 In any event, the glucocorticoid replacement is non-physiological with altered diurnal rhythm of cortisol availability. [16][17][18]20,21 In the females with primary adrenal insufficiency, the lack of dehydroepiandrostendione (DHEA) may play a role for the QoL 22-24 although debated. 25 Additionally, reduced adrenaline secretion from the adrenal medulla is suspected to contribute to a poor performance [26][27][28] but also debated. ...
Appropriate management of adrenal insufficiency in pregnancy is challenging due to the rarity of both primary, secondary, and tertiary forms of the disease and the lack of evidence-based recommendations to guide clinicians to glucocorticoid and sometimes also mineralocorticoid dosage adjustments. Debut of adrenal insufficiency during pregnancy requires immediate diagnosis as it can lead to adrenal crisis, intrauterine growth restriction, and foetal demise. Diagnosis is difficult due to the overlap of symptoms of adrenal insufficiency and its crisis with those of pregnancy. Adrenal insufficiency in stable replacement treatment needs careful monitoring during pregnancy to adapt to the physiological changes in the requirements of the adrenal hormones. This is hampered because the diagnostic threshold of most adrenocortical hormones is not applicable during pregnancy. The frequent use of assisted reproduction technology with controlled ovarian hyperstimulation in these patient groups with disease-induced low fertility has created an unrecognised risk of adrenal crises due to accelerated oestrogen stimulation with an increased risk of even life-threatening complications for both the woman and foetus. The area needs consensus recommendations between gynaecologists and endocrinologists in tertiary referral centres to alleviate such increased gestational risk. Patient and partner education and the use of the EU emergency card for the management of adrenal crises can also contribute to better pregnancy outcomes. There is a strong need for more research on, for example, the improvement of glucocorticoid replacement as well as crisis management treatment and biomarkers for treatment optimization in this field, which suffers from the rare nature of the diseases and poor funding.
... However, the mechanisms by which GC therapy increases mortality risk have not been fully clarified. A major burden for long-term GC regimens is the difficulty of perfectly matching the distinct circadian rhythm of circulating cortisol levels, and another issue is that the current dose equivalents of GCs used for replacement/therapy are based on the potency of anti-inflammatory action, not equivalent cardiovascular and bone safety effects [9]. The last issue is the insufficient scientific evidence regarding when to discontinue GCs, how rapidly to taper the dosage of GCs, and what are the differences among different GCs (e.g., cortisone, prednisone, dexamethasone, and triamcinolone). ...
... While this observation might reflect a genuine age-related difference exerted by the underlying disease, it is plausible that this discrepancy might relate to the long-term therapeutic (perhaps supraphysiological) exposure to GCs. As discussed above, GC treatment often fails to replicate physiological circadian rhythms [179], resulting in times of under-or overtreatment, both of which can negatively impact cognitive function [177], especially memory [180]. Recent observations have also reported significantly lower IQ in poorly controlled patients affected by SW-CAH, with multivariate analysis showing that in addition to androgen levels and hyponatraemic episodes, higher GC doses were associated with cognitive impairment [163]. ...
Purpose:
The hypothalamic-pituitary-adrenal (HPA) axis exerts many actions on the central nervous system (CNS) aside from stress regulation. Glucocorticoids (GCs) play an important role in affecting several cognitive functions through the effects on both glucocorticoid (GR) and mineralocorticoid receptors (MR). In this review, we aim to unravel the spectrum of cognitive dysfunction secondary to derangement of circulating levels of endogenous and exogenous glucocorticoids.
Methods:
All relevant human prospective and retrospective studies published up to 2022 in PubMed reporting information on HPA disorders, GCs, and cognition were included.
Results:
Cognitive impairment is commonly found in GC-related disorders. The main brain areas affected are the hippocampus and pre-frontal cortex, with memory being the most affected domain. Disease duration, circadian rhythm disruption, circulating GCs levels, and unbalanced MR/GR activation are all risk factors for cognitive decline in these patients, albeit with conflicting data among different conditions. Lack of normalization of cognitive dysfunction after treatment is potentially attributable to GC-dependent structural brain alterations, which can persist even after long-term remission.
Conclusion:
The recognition of cognitive deficits in patients with GC-related disorders is challenging, often delayed, or mistaken. Prompt recognition and treatment of underlying disease may be important to avoid a long-lasting impact on GC-sensitive areas of the brain. However, the resolution of hormonal imbalance is not always followed by complete recovery, suggesting irreversible adverse effects on the CNS, for which there are no specific treatments. Further studies are needed to find the mechanisms involved, which may eventually be targeted for treatment strategies.
... Cardiovascular disease is the main cause of death in AI patients (12), with comorbidities largely accounting for the increase in mortality. GC replacement therapy itself (in particular HC doses > 20 mg/d) adversely affects some of the well-known risk factors for cardiovascular disease (CVD), for example, obesity, hypertension, diabetes, and hyperlipoproteinemia (8,13,14). Temporary hypocortisolism may lead to subsequent increase of inflammatory markers being involved in atherosclerosis such as Interleukin 1 (IL-1), Interleukin 6 (IL-6), and tumor-necrosis factor (TNF) (15)(16)(17)(18). ...
Patients with adrenal insufficiency (AI) are treated with conventional or modified-release glucocorticoid (GC) replacement therapy (GRT). Although current GRT regimens aim to mimic the physiological circadian pattern of cortisol secretion, temporary phases of hypo- and hypercortisolism are common. There is good evidence that prolonged phases of hypo- or hypercortisolism are associated with impaired cognitive functioning. However, little is known about cognitive functioning in patients with AI regarding the effects of dosage and duration of glucocorticoid replacement therapy. There is also little data available comparing the effects of GC therapy on patients with primary and secondary forms of AI as well as with respect to different formulas. This Mini-Review gives an overview of the current studies on GRT for primary and secondary AI and their impact on cognition. Strengths and weaknesses of the studies and their Implications for clinical daily routine are discussed with a special emphasis on practical considerations for the treating endocrinologist.
... This last observation certainly requires further investigation. It is well-known that currently used glucocorticoid replacement regimens are frequently not physiological, not always reliably monitored with adequate markers, and many times overdosed [111]. Therefore, there is a consequent increased risk for metabolic and cardiovascular disorders recognized as risk factors for poor outcomes and death in COVID-19 [112]. ...
There is increased interest related to the impact of coronavirus disease 19 (COVID-19) on the endocrine system and in particular on the pituitary gland. Over the course of the severe infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there are both acute and delayed effects on the pituitary, related to infection and/or treatment. Hypopituitarism, pituitary apoplexy and hypophysitis have been all reported, as well as arginine vasopressin deficiency (diabetes insipidus) and syndrome of inappropriate antidiuretic hormone secretion. Furthermore, patients with acromegaly, Cushing's disease and hypopituitarism are theoretically at increased risk of complications with COVID-19 and require close monitoring. Evidence regarding pituitary dysfunction in patients with COVID-19 continues to be gathered, as the breadth and depth of knowledge also continues to rapidly evolve. This review summarizes data analysis to date on the possible effects of COVID-19 and COVID-19 vaccination on patients with normal pituitary function and patients with known pituitary pathology. Though clinical systems were significantly affected, it seems there is no overall loss of biochemical control in patients with certain pituitary pathologies.
... Patients who are on replacement therapy appear to have high mortality. This has been proposed to be mainly caused by the cardiovascular risk (CVR) of GC replacement therapy [14][15][16]. HC at a dose >20 mg/day seems to increase CVR (9). A population-based study has shown an increased CVR and cerebrovascular risk in individuals taking GCs compared with matching controls without GC intake [17]. ...
Adrenal insufficiency is a rare disorder that results from etiological factors affecting either the hypothalamic-pituitary axis or the adrenal gland itself. Studies have associated an inherently increased risk of cardiovascular events with this condition. It is treated with exogenous steroid supplementation. However, in recent years, there have been an increasing number of reports regarding the potential of steroid therapy to precipitate acute cardiac events. However, this risk is generally assumed to be dose-dependent and could be absent in patients receiving low-dose glucocorticoid treatment. We present a case of a 71-year-old woman who was admitted to our institution with bilateral lower limb swelling. Blood investigation revealed hypoalbuminemia and hyponatremia. Upon further evaluation she was diagnosed to have adrenal insufficiency and was started on hydrocortisone replacement therapy; however, the patient developed non-ST-segment elevation myocardial infarction (NSTEMI) and acute pulmonary edema a few days after starting steroid replacement therapy. Here, we discuss the possible association between hydrocortisone use and the development of acute cardiac events.
... Clinically relevant glucocorticoid-induced adrenal insufficiency has been documented in numerous cases of adrenal crises (50). English (52) and Danish (90) population-based register studies further described higher mortality (52) and incidence rates of As illustrated in both patient cases, fatigue is a predominant complaint in adrenal insufficiency (65,95,99,100). Daily variation in fatigue depending on stress level and how closely the replacement regimen mimics the natural circadian cortisol rhythm have been reported in patients with primary and secondary adrenal insufficiency (95,(99)(100)(101)(102), but has not been investigated in A c c e p t e d M a n u s c r i p t 19 patients with glucocorticoid-induced adrenal insufficiency. Such symptom variation during the day might not be captured in retrospective questionnaires using a long recall period. ...
... English (52) and Danish (90) population-based register studies further described higher mortality (52) and incidence rates of As illustrated in both patient cases, fatigue is a predominant complaint in adrenal insufficiency (65,95,99,100). Daily variation in fatigue depending on stress level and how closely the replacement regimen mimics the natural circadian cortisol rhythm have been reported in patients with primary and secondary adrenal insufficiency (95,(99)(100)(101)(102), but has not been investigated in A c c e p t e d M a n u s c r i p t 19 patients with glucocorticoid-induced adrenal insufficiency. Such symptom variation during the day might not be captured in retrospective questionnaires using a long recall period. ...
Glucocorticoid-induced adrenal insufficiency is caused by exogenous glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis and is the most prevalent form of adrenal insufficiency. The condition is important to diagnose given the risk of life-threatening adrenal crisis and impact on patients' quality of life. The diagnosis is made with a stimulation test such as the ACTH-test. Until now, testing for glucocorticoid-induced adrenal insufficiency is often based on clinical suspicion rather than routinely, but accumulating evidence indicates that a significant number of cases will remain unrecognized. During ongoing oral glucocorticoid treatment or initially after withdrawal ~50% of patients have adrenal insufficiency, but outside clinical studies ≤1% of patients have adrenal testing recorded. More than 70% of cases are identified during acute hospital admission where the diagnosis can easily be missed as symptoms of adrenal insufficiency are non-specific and overlap those of the underlying and intercurrent conditions. Treatment of severe glucocorticoid-induced adrenal insufficiency should follow the principles for treatment of central adrenal insufficiency. The clinical implications and thus indication to treat mild-moderate adrenal deficiency after glucocorticoid withdrawal is not established. Also, the indication of adding stress dosages of glucocorticoid during ongoing glucocorticoid treatment remains unclear. In patients with established glucocorticoid-induced adrenal insufficiency, high rates of poor confidence in self-management and delayed glucocorticoid administration in the acute setting with an imminent adrenal crisis call for improved awareness and education of clinicians and patients. This article reviews different facets of glucocorticoid-induced adrenal insufficiency and discusses approaches to the condition in common clinical situations.
... 90 minutes) it is usually given twice or thrice daily, guided by the circadian rhythm of cortisol secretion (two thirds of the total daily dose in the morning, one third in the early afternoon) (22,24,25). However, pronounced fluctuations of serum cortisol ranging from supraphysiological to almost undetectable levels have been reported with this therapy regimen (27,28). A modified-release hydrocortisone is designed to more closely resemble the physiological cortisol profile (29). ...
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health crisis affecting millions of people worldwide. SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2) after being cleaved by the transmembrane protease serine 2 (TMPRSS2). In addition to the lung, gastrointestinal tract and kidney, ACE2 is also extensively expressed in endocrine tissues, including the pituitary and adrenal glands. Although glucocorticoids could play a central role as immunosuppressants during the cytokine storm, they can have both stimulating and inhibitory effects on immune response, depending on the timing of their administration and their circulating levels. Patients with adrenal insufficiency (AI) or Cushing’s syndrome (CS) are therefore vulnerable groups in relation to COVID-19. Additionally, patients with adrenocortical carcinoma (ACC) could also be more vulnerable to COVID-19 due to the immunosuppressive state caused by the cancer itself, by secreted glucocorticoids, and by anticancer treatments. This review comprehensively summarizes the current literature on susceptibility to and outcome of COVID-19 in AI, CS and ACC patients and emphasizes potential pathophysiological mechanisms of susceptibility to COVID-19 as well as the management of these patients in case of SARS-CoV-2. Finally, by performing an in silico analysis, we describe the mRNA expression of ACE2, TMPRSS2 and the genes encoding their co-receptors CTSB, CTSL and FURIN in normal adrenal and adrenocortical tumors (both adenomas and carcinomas).
