Abstract

Background: Patients with adrenal insufficiency (AI) have been treated with oral administration of hydrocortisone (HC). It has been observed that general well-being is not fully restored by this supplementation. Hence, dual-release HC preparation and continuous subcutaneous HC infusion have been used to simulate endogenous secretory rhythm of cortisol. Another inadequacy is inability to supply enough cortisol to the medulla for sufficient adrenaline (AD) biosynthesis. Low urinary excretion and low blood levels of AD have been observed in patients with Addison’s disease maintained on HC supplementation. We suspected AD deficiency might be a cause of the persistent symptoms.

Method: AI was diagnosed in 32 patients, which was based on 30-min cortisol levels of low-dose corticotropin test <20 µg/dl and amelioration of symptoms other than fatigue and difficulty wakening up after HC. Fatigue and difficulty wakening up have persisted in eight patients even after increasing HC doses up to twofold. Plasma catecholamine levels were measured in 16 of the 32 patients, i.e. four with persistent fatigue, one with fatigue and difficulty wakening up, and eleven without persistent symptoms.

Result: The AD levels of 16 patients [<10 (N=5)-60 pg/ml] were lower than those of the 20 controls [<10 (N=2)-80 pg/ml]. The AD levels of five patients with persistent fatigue [<10 (N=4) and 20 pg/ml] were much lower than those of the patients without persistent symptoms [<10(N=1) -60 pg/ml]. Noradrenaline levels were not different between any two groups.

Conclusion: AD deficiency is possibly related to persistent fatigue.

Keywords

Adrenal insufficiency; Fatigue; Difficulty wakening up; Adrenaline; Cortico-medullary collaboration

Abbreviation

HCS-Hydrocortisone supplementation

Background

Most patients suspected of adrenal insufficiency (AI) are diagnosed and treated in following way. Patients present with symptoms of one or more organ systems; some patients present as latent AI, i.e. afflicted patients are un-aware of or overlooking symptoms and lead a normal life in the absence of physical or psychosocial stress [1]; when either morning cortisol or ACTH levels are preliminarily measured, morning cortisol levels <140 nmol/L (5 µg/d) [2], <4 µg/dl [3], and morning ACTH levels above the 2-fold of the upper limit of reference value [2] are considered highly suspicious of AI; the diagnosis of AI is confirmed usually by 250-µg corticotropin test (standard test, ST) and patients are tentatively supplemented with weight-based quantity hydrocortisone (HC) [4] with or without fludrocortisone. If symptoms are alleviated, they are maintained on HC.

A few groups of endocrinologists have observed incomplete restoration of general well-being in patients treated with HC in this way [5-7]. As endogenous rhythm of cortisol secretion cannot be restored by the intermittent oral administration of HC, dual-release tablets of HC [8,9], continuous subcutaneous HC infusion [10-12], and pulsatile subcutaneous HC infusion [13] were employed to simulate endogenous cortisol rhythmicity. Studies by questionnaire proved the scores of health-related quality of life were raised after continuous subcutaneous HC infusion [10-12].

We have diagnosed AI in more than 40 patients with AI as described in method section. They have been maintained on weight-based quantity of HC in two or three unequally divided doses [4]. To examine whether every symptom has ameliorated after HC supplementation (HCS), symptoms of 32 patients having been maintained on HCS for more than six months at our outpatient clinic were assembled and classified into two categories, i.e. persistent and ameliorated.

Urinary Adrenaline (AD) excretion is reduced in patients with AI supplemented with HC [14], Blood AD levels are reduced in patients with Addison’s disease [15] as well as in those with classic 21-hydroxylase deficiency [16] while being maintained on HCS. Clinical implications of these observations remain unknown. By oral administration of HC, enough cortisol cannot be supplied to the medulla needed for sufficient AD biosynthesis (cf. discussion section), we suspected AD deficiency might be a possible cause of persistent symptoms. Plasma catecholamine levels were measured in half of the 32 patients with AI.

Materials and Methods

This is a clinical observational study dealing with 32 patients having been maintained on HCS at our outpatient’s clinic. When patients came or were referred to us, they were evaluated for symptoms suggestive of dysfunction of one or more organ systems. In patients with autoimmune thyroid disease, co-existing symptoms unrelated thyroid disease were inquired [17]. If no cause of symptoms was discovered after history and physical examination, ordinary laboratory studies, and, if necessary, endoscopic examination, they were screened with morning cortisol levels. As the mean precorticotropin test cortisol levels of 20 control subjects was 11.7 µg/dl (cf. result section), we set cutoff cortisol level for the screening at 12 µg/dl. The screening by cortisol levels was omitted in some patients if AI appears likely from history. Past history of prolonged steroid treatment was inquired in case of low cortisol levels. Then, cortisol secretory reserve was assessed by 1-µg corticotropin test (low-dose test, LDT). In case 30-min cortisol levels were below the cutoff value set at 20 µg/dl (cf. result section), patients were tentatively treated with hydrocortisone (HC) of 15 mg/day for bodyweight of 55-74 kg in two or three unequally divided doses [4] with or without fludrocortisone 0.1 mg/day. After amelioration of somatic symptoms (cf. the result section) were ascertained, patients have been maintained on HCS. Anti-21hydroxylase auto-antibodies was not measured.

LDT was done at outpatient clinic starting at around 9:00 AM. Blood samples for cortisol levels were drawn before, 30-min, and 60 min of i.v. injection of 1-µg corticotropin (synthetic subunit of ACTH,^1-24 ACTH, Alfresa Pharma, Osaka, Japan). Blood samples for ACTH measurement were drawn only before the injection. ACTH and cortisol levels were measured by Eclusys ACTH (Roche Diagnostics) and Chemilumi cortisol2 (Siemens Health Care Diagnostics), respectively. Both assays were performed by Biochemical Laboratories (Saitama, Japan). Twenty healthy subjects consisting of two men and eighteen women (age: mean 47.7 years; range 24 to 76 years) underwent LDT. They denied history of illness requiring prolonged steroid treatment. They gave informed consent before LDT.

When measurement of plasma catecholamine levels was proposed, 16 of the 32 patients, five with persistent fatigue and 11 without fatigue, cooperated with the proposed test. One of the five patients, a junior student, had difficulty wakening as well. Seven of the 11 patients admitted to amelioration of fatigue after HCS and other four did not have fatigue before HCS. Other patients did not agree with the measurement. The catecholamine data of patients with adrenal incidental tumor (probed to be hormonally inactive) for endocrine screening were used for controls. Blood for catecholamine measurement was drawn in EDTA-containing tubes, plasma was separated without delay, and stored frozen until assay. Catecholamine levels were assayed by high-performance liquid chromatography with electrochemical detection by Biomedical Laboratories.

Results

The cortisol responses to LDT of patients are illustrated with 95% confidence interval (CI) of 20 controls’ levels (Figure 1). As 95% CI of their 30-min cortisol levels were 21.5-23.9 µg/dl, cutoff level of normal cortisol response was set at 20 µg/dl. The diagnosis of AI was made by 30-min cortisol levels below the cutoff level and amelioration of somatic symptoms (cf. the second paragraph below).

Figure 1: Cortisol Responses to Low-dose Corticotropin Test.
The Data of LDTs are plotted in diagrams with time on abscissa and cortisol level on ordinate. 95 % confidence interval of controls (N=20)’ responses is shown by shaded area.

The 0-min cortisol and ACTH levels of LDT were compared between the patients and the controls (Figure 2). Only two patients had low 0-min cortisol levels, 3.4, 3.8 µg/dl, which were lower than controls’ levels, i.e. mean, 11,7 µg/dl, range 4.5-18.6 µg/dl (Panel a). The ACTH levels of the patients distributed in the wide range from 9.2 pg/ml to 58.6 pg/ml (Panel b). Only seven patients showed ACTH levels above the controls’ range, 18.1-23.1 pg/ml. The ACTH levels of three patients were 9.3, 9.2, 10.5 pg/ml. Their AI was primary because their ACTH levels were raised to 201, 341, and 219 pg/ml, respectively, by insulin-induced hypoglycemia test in later period.

Figure 2: Cortisol and ACTH Levels of before Corticotropin Injection of Patients and Controls.
Panela, pretreatment cortisol levels of patients and controls Panelb, pretreatment ACTH levels of patients and controls.

The demographic data and symptoms were summarized in table 1. Eighteen patients (56.2 %) complained fatigue before HCS but none was troubled solely by fatigue. Other frequent symptoms were gastrointestinal symptoms, lightheadedness, syncope, and coolness of the hands and feet. Gastrointestinal symptoms often exacerbated when encountered on summer heat, grief, or troubles at workplaces. Four patients had kinds of musculoskeletal symptoms. They showed negative serology tests to rheumatic diseases and their symptoms were unresponsive to non-steroidal anti-inflammatory agents. Three patients with history of gastrectomy years ago were evaluated for recent onset of late damping syndrome and AI was proved to be the cause of hypoglycemia. Hemodialysis sessions had often to be terminated in one patient because of blood pressure drop. Four patients attending junior high school were thought to have orthostatic dysregulation [18]. Orthostatic circulatory change per se did not much influence their daily lives. Besides frequent absence from school because of difficulty wakening up, they were troubled fatigue, vomiting, diarrhea, or coolness of hands and feet. They were referred from pediatric clinic for possible AI.

Gastrointestinal symptoms, musculoskeletal symptoms, syncope, coolness of hands and feet, were ameliorated within a few months of HCS. Lightheadedness or syncope of two patients disappeared following supplementation of fludrocortisone of 0.1 mg/day added to HC. Hypoglycemia ceased to recur. Hemodialysis session had no longer to be interrupted. Fatigue of six adult patients and fatigue as well as difficulty wakening up of two junior students have persisted even after increasing HC doses up to twofold. To summarize the above findings, somatic symptoms were ameliorated after HCS in every patient and behavioral symptoms persisted after HCS in eight patients.

The catecholamine data of patients with AI and controls are illustrated in figure 3. The AD levels of five patients with persistent fatigue were lower than the levels of 11 patients without fatigue (p<0.01, Wilcoxon test) and the AD levels of both categories of patients were lower than the levels of controls (p<0.05, Wilcoxon test) (Panel a). The levels of noradrenaline were not significantly different between any two groups (p>0.05, Wilcoxon test) (Panel b). The 0-min cortisol levels of the five patients with persistent fatigue were lower than those of 11 patients without fatigue, i.e. 6.7, 3.8-8.1 µg/dl (mean, range)vis8.6, 4.8-12.2 µg/dl but the levels were not significantly different between patients with fatigue and those without fatigue (p>0.05, Wilcoxon test).

Figure 3: Plasma Catecholamine Levels of Patients and Controls.
Panel a, adrenaline level of patients with persistent fatigue, patients without fatigue, and controls Panel b, noradrenaline levels of patients with persistent fatigue, patients without fatigue, and controls.

Discussion

The AI of the 32 patients was based on insufficient cortisol response to LDT and amelioration of somatic symptoms. The cortisol levels were low in two patients and the ACTH levels were above controls’ levels in seven patients (Figure 2). LDT was employed to prove AI instead of ST in this study. Not a few endocrinologists may disagree with the diagnosis of AI. Annotation is needed for our diagnostic methods.

First, two guidelines of diagnosis and treatment of AI [2,3] have not designated the lowest ACTH level as an exclusion item of AI. Normal ACTH levels were reported in patients with anti-adrenal autoantibodies [19] as well as in patients with preclinical Addison’s disease [20]. Corrado Betterle and his coworkers postulated advancement of autoimmune adrenal disease in four stages with the stage two being characterized by normal ACTH and cortisol levels [21]. As the cortisol levels of most of the present patients were in the range of the controls, their AI was considered to be in the early stage. Second, LDT was employed for the cortisol response to corticotropin instead of ST recommended in two guidelines [2,3]. There are several studies of relative utility of two tests. Most of them were done in patients with secondary AI. The relative utility was studied in patients with primary AI by two groups of investigators [22, 23]. Dekkers, et al. [23] studied LDT and ST separately by at least 7 days in 98 patients suspected of primary AI. They used cortisol levels >20 µg/dl as a cutoff level. They found four kinds of cortisol responses: (a) abnormal cortisol response to both tests in 17 patients, (b) abnormal cortisol response to the LDT and normal response to ST in 11 patients, (c) normal response to both tests in 65 Patients, (d) normal response to LDT and abnormal response to ST in 5 patients. Twenty-eight patients having shown either type (a) or type (b) cortisol responses are diagnosed as AI. If Dekkers’ patients with (b) type of cortisol response are tested solely by ST, 11 of 98 patients (11.2%) would be not diagnosed as AI. We suppose patients in early stage of AI maintain responsiveness to high-dose corticotropin and may show normal cortisol response to ST. The comparison of usefulness of LDT and ST remains to be studied in early-stage AI as well as in advanced stage AI.

The 32 patients presented with 13 kinds of symptoms and none had hyperpigmentation (Table 1). Their symptoms were non-specific and not helpful to pursue AI. Stress-associated presentation or exacerbation of symptoms, symptoms of patients with autoimmune thyroid disease unexplained by thyroid illness [17] can be clues to pursue AI. Somatic and behavioral symptoms differ in presentation, i.e. the former are manifested by the dysfunction of one or more organs and the latter present as altered behavior insufficiently compatible with daily lives. The difference of presentation suggests HC deficiency per se may not be associated with behavioral symptoms. Walter Cannon proposed “excited behavior in fight or flight reaction is accompanied by augmented AD secretion” [24]. Is the contraposition of this proposition true? That is, is insufficient secretion of AD associated with downhearted behavior?

	Age/ Gender	Persistent	Ameliorated
patient 1*	47/W		weight-loss, non-rheumaticfingerstiffness, polyarthralgia
patient 2	27/W		fatigue, anorexia, weakness, hypoglycemia
patient 3*	59/W		non-rheumatic  finger  swelling  and  pain,  swelling  of forearms
patient 4	56/M		fatigue, light-headedness, coolness of hands and feet
patient 5*	68/W		fatigue, anorexia, history of heat exhaustion
patient 6	52/W	fatigue	weight-loss, anorexia
patient 7*	26/W	fatigue	anorexia, weakness, syncope
patient 8*	13/M		fatigue,epigastric pain, vomiting, diarrhea, syncope, dif. wakening up, OD
patient 9*†	13/W	fatigue, dif. wakening up	vomiting, epigastric pain, syncope, OD
patient 10*†	32/W		fatigue, nausea, abdominal pain, frequenrt diarrhea
patient 11†	49/M		frequent diarrhea
patient 12	57/W		non-rheumatic  swelling  and  pain  of  interphalangeal joints
pateint 13*	48/W	fatigue	weight-loss, abdominal pain, diarrhea
patient14	54/M		frequent diarrhea
patient 15	36/M		nausea, frequent diarrhea
patient 16	28/M	fatigue	weight-loss,  anorexia, epigastric pain, frequent diarrhea
patient 17*	23/W		weight-loss,    fatigue,    anorexia,    diarrhea,    syncope, hypoglysemia
patient 18*†	55/M		weight-loss, epigstric pain, frequent diarrhea
patient 19*	18/W		fatigue, dif. wakening up,  light-headedness, coolness of hand & feet, OD
patient 20	35/M		hypoglycemia (presumably related aled to Prader-Willi syndrome)
patient 21†	62/M		weight-loss, fatigue, hypoglycemia due to late damping syndrome
patient 22	24/M		fatigue, frequent diarrhea, light-headedness, coolness of hands and feet
patient 23*	41/W		fatigue, light-headedness, coolness of hands and feet
patient 24*	14/W	fatigue, dif. wakening up	nausea, frequent diarrhea, OD
patient 25	69/W		frequent diarrhea
patient 26*	78/M	fatigue,	heat    exhaustion    (slow    recovery    following    usual treatment)
patient 27	68/M		hypoglycemia due to late damping syndrome
patient 28*	70/M		non-rheumatic myalgia
patient 29	66/M		hypoglycemia due to late-dumping syndrome
patient 30*†	45/M	fatigue	frequent diarhea
patient 31	47/M		heat    exhaustion    (slow    recovery    following    usual treatment)
patient 32*	57/M		fatigue, recurrent hypotension during hemodialysis
abbreviations: W, woman: M, man; dif, difficulty; OD, orthostatic dysregulation
*plasma catecholamine levels  measured, †comorbid autoimmune thyroid disease

Table 1: Changes of Symptoms after Hydrocortisone Supplementation.

There are histological and biochemical evidences of corticomedullary collaboration and cortisol’s trophic role in the biosynthesis of AD: the medulla is entirely enclosed by the cortex; consequently, the medulla is irrigated bycortisol-rich blood via adrenal portal system [25], which is considered to be required to keep sufficient activity of adrenaline-synthesizing enzyme, i.e. phenylethanolamineN-methyltransferase, in the medulla [26]. Provided the corticomedullary collaboration is functional in man, it is understandable that sufficient AD is not produced because of insufficient supply of cortisol for medullary AD biosynthesis by oral administration of HC and that insufficient AD production is a possible cause of persistent fatigue. Diurnal variation of plasma AD levels with trough during sleep and gradual rise in the morning hours is reported in normal subjects [27]. Failure of timely and sufficient AD secretion is a possible cause of difficulty wakening up of junior students.

There are some limitations in this conclusion. As data of adrenal incidentaloma screening were used for “controls”, the “controls” were not controls in usual sense. The ranges of AD and noradrenaline of the “controls” were <10-80 pg/ml, 100-700 pg/l, respectively. As these ranges are not much different from controls’ AD and noradrenaline levels reported by Merke at al., i.e. 39 ± 23 pg/ml, 187 ± 45 pg/ml, respectively [16]. Using the data of adrenal incidentaloma screening as “controls” appears acceptable. The number of the patients studied by catecholamine measurement was small. AD levels below the assay sensitivity were also observed in one patient without fatigue as well as in two of the controls. Plasma AD levels are generally low in comparison noradrenaline levels and it is difficult to measure AD concentration of plasma containing AD less than 100 pg/ml with two significant digits by current assay method. Therapeutic trial with AD receptor agonists is awaited.

Lastly, we have observed persistent fatigue in three patients after hemiadrenalectomy for Cushing syndrome. Their fatigue was possibly associated with adreno-medullary insufficiency. Proper attention is to be paid to persistent fatigue of patients with post-hemiadrectomy.

Conclusion

Somatic symptoms were ameliorated by HCS but behavioral symptoms persisted. The systemic administration of HC cannot sufficiently supply cortisol-rich blood to the medulla for AD synthesis. The persistent behavioral symptoms appear attributable to impaired medullary AD biosynthesis. This conclusion remains to be confirmed in more patients. AD receptor agonists possibly improve quality of life of AI patients.

Acknowledgements

The authors declare that they have no conflict of interest. This observation study was examined and approved by in-hospital clinical ethics committee (certificate number. 2023-003). Its publication is approved by all authors. The study did not receive any specific grant from funding agencies in public, commercial, or not-for-profit sectors.

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Article Information

Article Type: RESEARCH ARTICLE

Citation: Yamamoto T, Ishigaki S, Uryu K, Harada H (2024) Persistent Symptoms of Adrenal Insufficiency after Hydrocortisone Supplementation: Is Adrenaline Deficiency a Cause?. Int J Endocrinol Metab Disord 8(1): dx.doi.org/10.16966/2380-548X.179

Copyright: © 2024 Yamamoto T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication history: 

Received date: 17 Nov, 2024

Accepted date: 20 Dec, 2024

Published date: 27 Dec, 2024