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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 675-680
Copyright © 2004 by The Endocrine Society

Adrenal Sensitivity to Adrenocorticotropin 1–24 Is Reduced in Patients with Autoimmune Polyglandular Syndrome

R. Giordano, M. Pellegrino, S. Oleandri, M. Baldi, M. Balbo, S. Laureti, A. Falorni, E. Ghigo and E. Arvat

Division of Endocrinology (R.G., M.P., S.O., M.Bald., M.Balb., E.G., E.A.), Department of Internal Medicine, University of Turin, Turin, Italy; and Department of Internal Medicine (S.L., A.F.), University of Perugia, Perugia, Italy

Address all correspondence and requests for reprints to: Emanuela Arvat, M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy. E-mail: emanuela.arvat{at}unito.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Autoimmune polyglandular syndromes are fairly common diseases that are classified into four constellations based on the clinical clustering of the various component diseases. In types 1, 2, and 4, primary adrenal insufficiency due to an autoimmune process is usually present, but its diagnosis is often delayed because it is difficult to detect in a subclinical phase. It is widely accepted that the classical dose of 250 µg ACTH1–24 is supramaximal, whereas 0.06 µg has been shown to be one of the lowest ACTH doses that is able to stimulate adrenal secretion in normal young subjects. The aim of this study was to clarify the sensitivity and maximal secretory response of the adrenal gland to ACTH in a group of patients with at least two autoimmune diseases, without clinical signs and symptoms of overt or subclinical hypocortisolism. Cortisol (F), aldosterone (A), and dehydroepiandrosterone (DHEA) responses to the sequential administration of very low and supramaximal ACTH1–24 doses [0.06 µg followed by 250 µg ACTH1–24 iv at 0 and +60 min] were studied in 18 patients with at least two autoimmune diseases (AP; age, 20–40 yr; body mass index, 22–26 kg/m2). The results in the patients were compared with the results recorded in 12 normal age-matched control subjects (CS; age, 22–34 yr; body mass index, 20–25 kg/m2). At baseline, ACTH levels in AP were within the normal range but higher (P < 0.05) than in CS, whereas F, A, DHEA, urinary-free F, and plasma renin activity were similar in both groups. F, A, and DHEA responses to ACTH were dose dependent in both groups. However, in AP, F, A, and DHEA levels showed no response to the 0.06-µg ACTH dose, which, in turn, elicited clear responses (P < 0.01) in CS. On the other hand, F, A, and DHEA responses to 250 µg ACTH in AP were not different from those in CS. In conclusion, patients with autoimmune diseases who displayed a normal basal adrenal function showed a loss of F, A, and DHEA response to the very low ACTH dose, although they were normal responders to the high ACTH dose. These data are likely to indicate that a reduced sensitivity to ACTH in all adrenal zones occurs in patients with different types of autoimmune disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AUTOIMMUNE POLYGLANDULAR SYNDROMES (APS) are fairly common diseases that are classified into four constellations based on the clinical clustering of the various components (1, 2, 3). The definition of the type of APS is clinically important in predicting the potential occurrence of other associated diseases in both patients and family members. In types 1, 2, and 4, primary adrenal insufficiency due to an autoimmune process is usually present, but its diagnosis is often delayed because it is difficult to detect in a subclinical phase (3, 4). In fact, in the early phase, APS patients show at least one clinical disease characteristic of the syndrome with one or more biochemical markers of the other components coupled with subclinical or normal function of the target organs (3, 4). Among biochemical markers, the detection of autoantibodies is considered to be relevant (3). In particular, detection of circulating adrenal autoantibodies against the steroidogenetic enzyme 21-hydroxylase autoantibody (21OHAb) is useful for early identification of patients at risk of developing an autoimmune Addison’s disease (5, 6, 7). However, it has been emphasized that adrenal autoantibodies are detected only in 1–2% of patients with different autoimmune diseases (5, 6, 7). Most of the symptoms of adrenal insufficiency are not specific and usually occur insidiously (8), and autoimmune Addison’s disease can develop slowly over many years before clear symptoms appear. Thus, a screening of patients with autoimmune diseases suspected for APS is needed for early diagnosis (3, 4). The first evidence of adrenal insufficiency is usually an increase of plasma renin activity (PRA) levels associated with low-normal or low aldosterone (A) levels. Later, ACTH increase becomes evident together with a low cortisol (F) response to ACTH stimulation. Finally, low F and urinary free F levels coupled with very elevated ACTH levels demonstrate overt adrenal insufficiency (8).

At present, 250 µg ACTH is the classical dose to test adrenal function in patients with suspected primary adrenal deficiency (9). This ACTH dose is extremely supramaximal, eliciting very high circulating ACTH levels (9, 10, 11, 12, 13). Similar to what is suggested for secondary adrenal deficiency, low ACTH doses have also been proposed to test the adrenal function in suspected primary adrenal insufficiency; in fact, low ACTH doses could better evaluate the adrenal sensitivity in the early phase of the disease (9, 12, 13).

In recent studies, Laureti et al. (14, 15) have shown that the 1.0-µg ACTH dose has high diagnostic sensitivity and specificity for primary adrenal insufficiency and can identify subjects with preclinical adrenal dysfunction. However, even 1.0 µg ACTH1–24 has to be considered a high dose; 0.06 µg is one of the lowest ACTH doses that is able to stimulate adrenal secretion in normal young subjects (16).

On the basis of previous studies, our aim was to verify the sensitivity and maximal secretory response of the adrenal gland to ACTH in a group of patients with at least two autoimmune diseases, without clinical signs and symptoms of overt or subclinical hypocortisolism. Our working hypothesis was that, despite a normal response to a high ACTH dose, patients with some subclinical adrenal insufficiency would display a precocious impairment of the adrenal sensitivity to corticotropin.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Drugs

Vials containing 250 µg of ACTH [ACTH1–24, tetracosactin; Synacthen] were purchased from Novartis-Pharma, Huningue, France.

The ACTH 250-µg dose was prepared by adding 250 µg to 2 ml sterile saline solution. For the ACTH 0.06-µg dose, 250 µg was diluted in a bottle containing 250 ml sterile saline solution and mixed thoroughly; 1 ml of this prepared solution containing 1 µg ACTH was added to 9 ml saline. Then we took 0.6 ml and added saline to obtain 1 ml of volume; the resulting solution was used immediately after preparation.

Study design

Eighteen autoimmune patients (AP) with at least two autoimmune diseases and without clinical signs and symptoms of overt or subclinical hypocortisolism (three males and 15 females; age, 20–40 yr; body mass index, 22–26 kg/m2), and 12 normal age-matched control subjects (CS; six males and six females; age, 22–34 yr; body mass index, 20–25 kg/m2) were studied. All women were studied in their early follicular phase; patients with premature ovarian failure were not on hormone replacement therapy at the time of the study. Patients with hypothyroidism, Basedow’s disease, hypoparathyroidism, or type 1 diabetes were under appropriate treatment with L-thyroxine, methimazole, calcium and vitamin D, or insulin at the time of the study. Patients with thyroid dysfunction had normal TSH, free T3, and free T4 levels; patients with hypoparathyroidism showed normal serum calcium and phosphate levels; and a good control of glycemic metabolism was present in patients with diabetes mellitus. Patients with inflammatory bowel disease or rheumatic disease had not been under steroid treatment for at least 1 yr; the previous treatment included immunosuppressive steroid doses. All subjects gave their informed consent to participate in the study, which was approved by the independent Ethical Committee of the University of Turin. Clinical and hormonal details of the patients are listed in Table 1Go.


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  		TABLE 1. Clinical features and basal hormonal values of AP and basal hormonal values of CS

 
All subjects were administered ACTH1–24 0.06 µg iv (at 0 min) followed by ACTH1–24 250 µg iv (at +60 min).

The tests were performed in the morning starting at 0830–0900 h after an overnight fasting. None of the subjects were on sodium restriction or potassium loading.

Blood samples for F, A, and dehydroepiandrosterone (DHEA) assay were collected at baseline (0 min) and then at +15, +30, +60, +90, and +120 min. At baseline, blood samples for ACTH and PRA and urinary samples for urinary-free F (UFC) were collected.

The patients were also studied for the presence of circulating adrenal autoantibodies directed against the steroidogenetic enzyme 21OH-hydroxylase.

Serum F (µg/liter; 2.7 µg/liter = 1 nmol/liter) was measured in duplicate by RIA (CORT-CTK125; DIA Sorin, Diasorin Diagnostics, Saluggia, Italy). The sensitivity of the assay was 11.0 µg/liter. The inter- and intraassay coefficients of variation ranged from 4.3–14.6% and from 4.2–8.96%, respectively.

Serum A (pg/ml; 2.7 pg/ml = 1 pmol/liter) was measured in duplicate by RIA (ALDO-MAIA; Biochem Diagnostics, Guidonia, Italy). The sensitivity of the assay was 16.2 pg/ml. The inter- and intraassay coefficients of variation ranged from 11.96–14.06% and from 4.21–9.57%, respectively.

Serum DHEA (µg/liter; 3.4 µg/liter = 1 nmol/liter) was measured in duplicate by RIA (DSL-9000 ACTIVE DHEA; Diagnostic Systems Laboratories Inc, Webster, TX). The sensitivity of the assay was 0.068 µg/liter. The inter- and intraassay coefficients of variation ranged from 5.6–10.6% and from 7.0–10.2%, respectively.

Plasma ACTH levels (pg/ml; 0.22 pg/ml = 1 pmol/liter) were measured in duplicate by immunoradiometric assay (Allegro HS-ACTH; Nichols Institute Diagnostic, San Juan Capistrano, CA). The sensitivity of the assay was 0.22 pg/ml. The inter- and intraassay coefficients of variation ranged from 2.4–8.5% and from 3.9–9.9%, respectively.

PRA levels [ng/ml·h; 0.27 ng/ml·h = 1 ng/(l*s)] were measured in duplicate by RIA (RENCTK; Diasorin Diagnostics). The sensitivity of the assay was 0.2 ng/ml·h. The inter- and intraassay coefficients of variation ranged from 9.27–21.12% and from 5.2–9.2%, respectively.

UFC (µg/24 h; 2.75 µg/24 h = 1 nmol/d) was measured in duplicate by RIA (Cortisol Bridge; Biochem Immunosystems Company, Milan, Italy). The sensitivity of the assay was 2.67 µg/24 h. The inter- and intraassay coefficients of variation ranged from 3.98–5.75% and from 2.64–8.67%, respectively.

21OHAb was determined in a radiobinding assay that uses in vitro translated recombinant human 35S-21OH. 21OHAb levels were expressed as a relative index (21OH index) based on the analysis of one positive and two negative standard sera included in each assay.

All samples from the same subject were analyzed together. The results are expressed as mean ± SEM or median and range of either absolute hormonal levels or {Delta} areas under the response curves, calculated by trapezoidal integration. The statistical evaluation was performed using nonparametric ANOVA (Kruskal-Wallis) and also the Wilcoxon or Mann-Whitney tests, when appropriate.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
At baseline, ACTH levels in AP were within the normal range but higher (P < 0.05) than in CS. However, F, A, DHEA, UFC, and PRA were similar in both groups (Table 1Go).

In AP, F, A, and DHEA levels showed no response to the 0.06-µg ACTH dose (Tables 2Go and 3Go, Figs. 1Go and 2Go). With respect to baseline, F and A levels showed a nonsignificant trend toward decrease, whereas DHEA levels showed a nonsignificant trend toward increase (Figs. 1Go and 2Go).


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  		TABLE 2. F, A, and DHEA responses (peaks) after 0.06 or 250 µg ACTH-(1–24) doses in AP and CS

 

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  		TABLE 3. F, A, and DHEA responses ({Delta}AUC) after 0.06 or 250 µg ACTH-(1–24) doses in AP and CS

 


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  		FIG. 1. Mean (± SEM) F, A, and DHEA levels after 0.06 µg followed by 250 µg ACTH doses in AP and CS. *, P < 0.05 vs. CS.

 


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  		FIG. 2. Mean (± SEM) F, A, and DHEA {Delta} areas under the response curves ({Delta}AUC) after 0.06 µg followed by 250 µg ACTH doses in AP and CS. *, P < 0.05 vs. CS.

 
However, the same ACTH dose elicited clear responses (P < 0.01) in CS (Tables 2Go and 3Go, Figs. 1Go and 2Go). On the other hand, F, A, and DHEA responses to 250 µg ACTH in AP were not different from the responses in CS, which were evaluated as both absolute peaks and {Delta} areas under the response curves (Tables 2Go and 3Go, Figs. 1Go and 2Go). None of the patients displayed positivity for 21OHAb (21OHAb index < 0.06).

Side effects

No side effects were recorded either in AP or CS after the administration of both ACTH doses.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present study demonstrate that patients with autoimmune diseases displaying normal basal adrenal function show a loss of F, A, and DHEA responsiveness to a very low ACTH dose, but they maintain a normal hormonal response to a supramaximal ACTH dose.

In some types of APS, a primary adrenal insufficiency can be present, but its diagnosis is often delayed because it is difficult to detect in a subclinical phase (3, 4).

The studies concerning the most appropriate methods to diagnose a subclinical adrenal insufficiency are controversial. It is widely accepted that the 250-µg ACTH dose is fairly supramaximal (9, 10, 11, 12, 13), and testing with low ACTH doses has been proposed as a more sensitive tool than ACTH 250 µg to explore the hypothalamus-pituitary-adrenal function, particularly in patients with suspected secondary adrenal insufficiency (10, 11).

Although 250 µg ACTH is the classical dose most often used, at present, there is no definite agreement about the best ACTH dose to evaluate adrenal function in subjects suspected of having primary adrenal insufficiency (9, 12, 13, 14, 15). It has been suggested that low ACTH doses can be useful even for the diagnosis of Addison’s disease, particularly in the preclinical phase. In fact, Laureti et al. (14, 15) have shown that 1.0 µg ACTH has high sensitivity and specificity in the diagnosis of preclinical primary adrenal insufficiency in patients at risk of developing the disease. However, even 1.0 µg ACTH has to be considered a high dose because 0.06 µg is one of the lowest ACTH doses that is able to stimulate adrenal secretion in normal young subjects (16). Moreover, a maximal F response has been shown to be coupled with circulating ACTH levels as low as 13–14 pmol/liter, which are fairly exceeded by the injection of an ACTH dose as low as 0.5 µg (9). In a previous dose-range study, we showed, in normal young subjects, that the maximal and the lowest stimulatory ACTH doses for F release are 1.0 µg and 0.03 µg, respectively; whereas A secretion is sensitive to the same lowest but not to the same maximal ACTH dose (25 µg was the maximal effective dose for this hormone) (16). The same study also showed that DHEA secretion is even more sensitive than F to ACTH stimulation (1.0 µg and 0.01 µg were the maximal and minimal effective doses).

As mentioned previously, submaximal more than maximal ACTH dose could be more useful in the evaluation of adrenal function in patients suspected for subclinical primary or secondary adrenal insufficiency (9, 10, 11, 12, 13, 14, 15). Based on this background, we have tested the adrenal sensitivity and the maximal secretory capacity by administering very low ACTH doses followed by supramaximal ACTH doses in a group of patients without clinical signs of adrenal insufficiency but with at least two autoimmune diseases; we considered these patients at higher risk of developing Addison’s disease as a component of APS.

The rationale for this sequential test comes from our previous demonstration that, in normal subjects, the adrenal response to high ACTH dose (administered consecutively after a very low dose) is not modified by the previous administration of an ACTH dose of 0.06 µg or less (although higher doses significantly decrease the adrenal response to a subsequent high ACTH dose) (16). Therefore, we proposed that the consecutive administration of a very low ACTH dose and a supramaximal ACTH dose would allow the evaluation of both adrenal sensitivity and the maximal secretory capacity of the adrenal gland to ACTH in a single testing session.

Our findings clearly show that, despite normal adrenal response to the highest dose, these patients are not sensitive to a very low ACTH dose. In fact, in AP, F, A, and DHEA showed no significant response to the very low ACTH dose in contrast with the clear response in CS. The lack of adrenal sensitivity to very low ACTH doses was coupled with a significant elevation in basal ACTH levels, thus reflecting the first stage of adrenal impairment. Accordingly, the increased ACTH levels would represent the first adaptation devoted to maintaining the adrenal function within the normal range. The normal response to the very high ACTH dose should not be a surprise because the dose is extremely supramaximal.

That adrenal insensitivity to very low ACTH doses reflects a first-step impairment in the adrenal cortex probably due to autoimmune disease seems questioned by the absence of adrenal autoantibody positivity. It has been emphasized that adrenal autoantibodies are detected only in 1–2% of patients with different autoimmune diseases, and approximately 40–50% of these adrenal autoantibody-positive patients progress toward clinical adrenal insufficiency (3, 5, 6, 7). However, the aim of this study was to identify a peculiar alteration, if any, in the adrenal sensitivity and/or secretory capacity in response to ACTH in patients with different autoimmune diseases, independently of the existence of adrenal antibodies. At present, we cannot define the clinical implications of these findings. However, given the interest of this observation, important information could arise in the future from the results of the currently ongoing prospective study.

On the other hand, we cannot rule out the possibility that this peculiar hormonal pattern may be due to the influence of the immune system on hypothalamic-pituitary-adrenal function. Several inflammatory mediators induced by the autoimmune processes are known to exert a stimulatory influence on the hypothalamic-pituitary-adrenal function (17, 18, 19), and this could explain the high basal ACTH levels in our group of patients. However, it has been shown that cytokines also have a direct stimulatory effect on adrenal secretion (17); this observation does not agree with our results, which show a reduced adrenal sensitivity to low ACTH dose in patients with autoimmune diseases. In contrast, some cytokines and other mediators of inflammation have been demonstrated to directly inhibit the adrenal function, giving support to our results (18, 19, 20). Finally, it may be hypothesized that a chronic corticotrope hyperactivation induced by the autoimmune process, also demonstrated by the high ACTH levels of our patients, could have, at least partially, desensitized the adrenal gland to ACTH stimulation.

Present results also provide a different picture from that observed in patients with secondary adrenal deficiency tested with the same experimental procedure. In fact, in hypopituitaric patients, a relative hypersensitivity of the adrenal gland to exogenous ACTH was present (21).

In conclusion, patients with autoimmune diseases displaying a normal basal adrenal function showed a loss of F, A, and DHEA response to the very low ACTH dose, although they were normal responders to a high ACTH dose. These data likely indicate that a reduced sensitivity to ACTH in all adrenal zones occurs in patients with different types of autoimmune diseases. In the future, the clinical implications of these findings could come from the results of the prospective study that is currently ongoing.


   Acknowledgments
 
We sincerely thank Dr. A. Bertagna, Mrs. A. Barberis, and M. Talliano for their skillful technical assistance.


   Footnotes
 
This work was supported by the University of Turin, the Foundation for the Study of Endocrine and Metabolic Diseases, and Ministry of University and Scientific Research Grant PRIN 2001063439.

Abbreviations: A, Aldosterone; AP, autoimmune disease patients; APS, autoimmune polyglandular syndromes; CS, control subjects; DHEA, dehydroepiandrosterone; F, cortisol; 21OHAb, 21-hydroxylase autoantibody; PRA, plasma renin activity; UFC, urinary-free cortisol.

Received May 9, 2003.

Accepted October 31, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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R. Giordano, M. Balbo, A. Picu, L. Bonelli, R. Berardelli, A. Falorni, E. Ghigo, and E. Arvat
Corticotrope hypersecretion coupled with cortisol hypo-responsiveness to stimuli is present in patients with autoimmune endocrine diseases: evidence for subclinical primary hypoadrenalism?
Eur. J. Endocrinol., September 1, 2006; 155(3): 421 - 428.
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