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First Department of Internal Medicine, Toho University School of Medicine (N.H., T.I., H.U., Y.M.), Tokyo 143-0015, Japan; and Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (N.H.), Bethesda, Maryland 20892-1583
Address all correspondence and requests for reprints to: Naoki Hiroi M.D., First Department of Internal Medicine, Toho University, 6-11-1 Omorinishi, Ota-ku, Tokyo 143-0015, Japan. E-mail: . n-hiroi{at}tkf.att.ne.jp
Abstract
To determine the efficiency of transmucosal absorption of ACTH, we measured serum cortisol, aldosterone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S) levels after intranasal (in) vs. iv administration of ACTH-(1–24) (250 µg) in 12 healthy adult men (mean age, 24.3 ± 3.2 yr; range, 21–31 yr), who had received no prior medication and had no symptoms of rhinitis. Blood was collected at 0, 30, 60, 120, and 180 min after administration of ACTH-(1–24), and the levels of adrenocortical steroids were measured by specific RIAs. There were no side-effects associated with in or iv ACTH administration. After in administration, serum cortisol and aldosterone increased rapidly by 224.7 ± 39.2% and 147.2 ± 50.5%, respectively, peaking 30 min after ACTH-(1–24) administration, and decreasing to basal levels within 120 min. These increases in serum cortisol and aldosterone were lower than those obtained after iv administration. Thirty minutes after in or iv administration of ACTH-(1–24), DHEA increased by 49.1 ± 27.2% and 81.6 ± 17.1%, respectively, and remained elevated for 180 min. Serum DHEA-S levels did not change after in administration of ACTH-(1–24) and increased only slightly after iv injection. Adrenocortical steroid levels did not increase after in administration of saline. These data demonstrate that adrenocortical steroids are stimulated by in administration of ACTH-(1–24). We suggest that intranasal administration of ACTH offers both a diagnostic approach as an adrenal function test and a therapeutic approach as ACTH replacement therapy in patients with ACTH deficiency. The latter may be more physiological than glucocorticoid replacement.
THE ADRENAL CORTEX of humans secretes three classes of steroid hormone: glucocorticoids (e.g. cortisol and corticosterone), mineralocorticoids (e.g. aldosterone), and androgens [e.g. dehydroepiandrosterone (DHEA)]. Glucocorticoids activate lipolysis, increase hepatic glucose production, stimulate the release of glucogenic amino acids from peripheral tissues such as skeletal muscle, and inhibit glucose uptake and utilization by peripheral tissues. In addition, glucocorticoids in excess suppress the immune response. Mineralocorticoids primarily influence fluid and electrolyte homeostasis. DHEA may influence atherosclerosis (1), help prevent diabetes mellitus (2), reduce fat mass (3), and improve immune function (4, 5) and may inhibit the development of cancer (6). In addition, it has been reported (7, 8) that DHEA replacement therapy improves well-being in the elderly.
Previous studies described elevated levels of cortisol and aldosterone after intranasal (in) ACTH administration, but to date DHEA and DHEA sulfate (DHEA-S) responses to in administration of ACTH have not been investigated (9, 10). The aim of this study was to examine the responses of cortisol, aldosterone, DHEA, and DHEA-S to in administration of ACTH-(1–24) in normal healthy volunteers.
Subjects and Methods
Subjects
Twelve normal volunteers (12 males) who had received no medication and had no rhinitis participated in this study. Their mean age was 24.3 ± 3.2 yr (range, 21–31 yr).
Solution preparation
The solutions for parental administration, iv, were prepared after appropriate dilution (vol/vol) of cortolocin (tetracosactide acetate, 0.25 mg/ml; Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan) in a 0.9% saline solution. The solutions of in administration consisted of 1) a saline solution control, and 2) cortolocin solution (0.25 mg/180 µl, wt/vol) in saline. A nasal spray (90 µl/dose) was used for intranasal administration.
Study design
An iv cannula was inserted in a forearm vein at 1800 h through which saline was infused to keep the line open. Subjects were rested for 30 min before starting the test at 1900 h and remained sitting through the test. A baseline blood sample was taken at 1900 h before ACTH-(1–24) (0.25 mg) or saline was administered by iv injection into a forearm vein or via nasal spray, and samples for steroid measurements were obtained at 30, 60, 120, and 180 min after administration. There was at least 1 wk between each study.
Hormone assays
All samples were centrifuged at 4 C, and plasma was separated and stored at -20 C until the time of assay. Plasma cortisol and DHEA-S were measured at each time point with commercially available RIA kits (Diagnostic Products, Tokyo, Japan), and aldosterone was determined at each time point by RIA kit (Dainabot Corp., Osaka, Japan). The intra- and interassay coefficients of variation in these kits were as follows: 4.3% and 5.2% for cortisol, 7.4% and 7.5% for DHEA-S, and 4.0% and 5.1% for aldosterone, respectively. Plasma DHEA was measured using a previously described technique (11) with minor modifications. The DHEA intra- and interassay coefficients of variation were between 7–8%.
Statistical analysis
Data were expressed as the mean ± SEM. Multiple comparisons were performed by two-way ANOVA, and individual differences were tested by Fisher’s least significance differences test after the demonstration of significant intergroup differences by ANOVA. Two-group comparisons were performed by paired t test. P < 0.05 was considered statistically significant.
Results
Figure 1
shows the percent increase in levels of four adrenocortical steroids, namely, cortisol, aldosterone, DHEA, and DHEA-S, after iv and in administration of ACTH. Cortisol levels were increased by 224.7 ± 39.2% (P < 0.001 vs. control) 30 min after in administration, and returned to baseline within 120 min. After iv administration of ACTH, cortisol levels increased by 276.1 ± 50.0% (P < 0.001 vs. control) within 30 min, and this level remained high during the rest of sampling period. After in saline administration, plasma cortisol levels decreased, as expected from the circadian variation in cortisol levels. Thirty minutes after in administration of ACTH, aldosterone levels increased by 147.2 ± 43.1% (P < 0.05 vs. control) and returned to baseline within 120 min. Aldosterone levels increased by 247.5 ± 50.0% (P < 0.001 vs. control) 30 min after iv infusion. Serum levels of aldosterone did not change after saline administration. DHEA increased significantly 30 min after in and iv administration of ACTH, whereas it remained at the same level until after 180 min (49.1 ± 27.2% and 81.6 ± 17.1%, respectively; P < 0.03 and P < 0.01 vs. control). Plasma DHEA-S levels did not change significantly after in saline or ACTH administration (6.1 ± 2.5%; P = NS vs. control); only a slight increase was observed after iv injection (22.1 ± 5.8%; P = NS vs. control).
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. The response of plasma cortisol to in ACTH-(1–24) administration (range of peak and incremental value, 604.0 ± 73.8 and 369.4 ± 65.7 nmol/liter, respectively) was significantly lower than that after iv administration [range of peak and incremental value, 929.0 ± 27.6 nmol/liter (P < 0.01 vs. in) and 676.1 ± 46.5 nmol/liter (P < 0.01 vs. in), respectively]. The peak and incremental aldosterone levels in response to intranasal ACTH-(1–24) administration (range of peak and incremental value, 430.5 ± 75.5 and 214.6 ± 70.2 pmol/liter, respectively; P < 0.001) were significantly lower after iv injection [range of peak and incremental value, 105.1 ± 22.2 pmol/liter (P < 0.05 vs. in) and 80.4 ± 16.6 pmol/liter (P < 0.01 vs. in), respectively]. The levels of DHEA were increased significantly after both in and iv administration of ACTH-(1–24) (range of peak value of intranasal and iv administration, 157.8 ± 12.6 and 96.1 ± 15.4 pmol/liter, respectively; P < 0.01 vs. in); the incremental values of DHEA were not significantly different between the intranasal and iv administrations (range of incremental value of intranasal and iv administration, 53.2 ± 8.4 and 41.2 ± 14.0 pmol/liter, respectively; P = NS). However, peak and incremental values of DHEA-S after in and iv administrations of ACTH-(1–24) were not increased.
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The present study shows that not only cortisol and aldosterone levels, but also DHEA levels increase significantly after in administration of ACTH-(1–24); however, DHEA-S levels remain constant. After in administration of ACTH-(1–24), the incremental values of the three adrenocortical steroids of interest, cortisol, aldosterone and DHEA, were significantly lower than those after iv injection.
Adelmann (10) reported that the levels of cortisol and aldosterone increased by approximately 30% and 20%, respectively, and returned to baseline within 180 and 120 min, respectively, after ACTH-(1–17) intranasal administration. Essentially, our data confirm this study. The higher bioactivity of ACTH-(1–24) than of ACTH-(1–17) is reflected in the greater percent increase in cortisol and aldosterone levels in our study. These data also confirmed the previous studies, which reported that urinary excretion of 17-ketosteroids and 17-ketogenic steroids increased approximately 50% after in administration of ACTH-(1–18) (9). Wuthrich et al. (12) have shown that the bioavailability of ACTH-(1–24) after in administration is approximately 4% of that after iv injection in rats.
The percent increase in DHEA levels in our study is lower than those in cortisol and aldosterone. Parker and Odell (13) demonstrated that the minimum effective dose of ACTH for DHEA stimulation (0.3 x 10-5 M) was 10,000-fold greater than the minimum effective dose for cortisol stimulation (0.3 x 10-9 M). Although ACTH is the strongest known modulator of DHEA secretion, several other hormones, including estrogens, PRL, GH, and gonadotropins, have been shown or postulated to modify adrenal androgen secretion (14). The DHEA-S response showed no significant increase after in or iv ACTH administration. However, although there was no detectable increase in DHEA-S 1 h after iv ACTH injection, after 12 h the levels of this hormone increased (15). In addition, after an iv bolus injection of ACTH-(1–24), plasma levels of DHEA-S did not change, but more prolonged administration of the peptide increased DHEA-S levels (16, 17). Normally, about half the DHEA synthesized in vivo is converted to DHEA-S, and much of the unconjugated steroid is converted extraadrenally to the sulfate, which accumulates at much higher levels in plasma than does the unconjugated steroid because of its lower clearance rate (16). The difference in the time of elevation of plasma DHEA and DHEA-S probably reflects the difference in their half-lives.
The mucosa of the nasal cavity has attracted great interest, mainly because of its relatively high permeability for peptides. The treatment of diabetes insipidus by in spray of 1-Deamino-8-D-arginine vasopressin has become standard therapy. Administration of gelified nasal insulin, a potential route for intensive insulin management, which is less invasive and more rapid than sc injection, is as efficient as sc administration of regular insulin in type 1 diabetic patients (18). Although normally ACTH is believed to be the primary modulator of cortisol secretion, this hormone stimulates the secretion of aldosterone, DHEA, and DHEA-S as well, and thus it could be used therapeutically as an alternative to glucocorticoid treatment in patients with ACTH deficiency and panhypopituitarism. Generally, DHEA and DHEA-S levels of such patients are low and remain low during glucocorticoid replacement therapy. ACTH administration, which therefore normalizes levels of all steroids including DHEA, is a reasonable alternative for physiological use in these patients. In addition, extraadrenal actions of ACTH have been reported on cardiovascular function, repair of nerve damage, and sexual responses (19). Thus, in application of ACTH might not only stimulate the secretion of adrenal steroids, but also influence extraadrenal functions. This route of ACTH administration is thus effective therapy in patients with ACTH deficiency.
Hypercortisolism in mental disease, as in melancholic depression, Alzheimer’s disease, and anxiety disorders, seems to preferentially reflect activation of hypothalamic CRH secretion (20, 21). CRH has been implicated in the causation of mental disorders. Intracerebroventricular administration of CRH to experimental animals produces a syndrome reminiscent of depression (22). Administration of a CRHR1 antagonist, on the other hand, significantly attenuates behavioral and neuroendocrinological responses to stress in primates and reduced depression and anxiety scores in patients with melancholic depression (23, 24). Two healthy volunteers had increased ACTH concentrations in their cerebrospinal fluid after in intake of ACTH. Acute intranasal administration of ACTH-(4–10) (1 mg) reduced negative processing of event-related brain potential, inducing diminished focus of attention (25). As secretion of CRH is regulated primarily by ACTH and cortisol, the concentration of ACTH in cerebrospinal fluid might, via a feedback mechanism, reduce the levels of CRH. In addition, as DHEA and its sulfate function as potent 
-aminobutyric acidA antagonists, correction of these neurosteroids might be effective in increasing neuronal excitability and enhancing learning and memory function (26).
In conclusion, levels of cortisol, aldosterone, and DHEA, but not DHEA-S, increase significantly after in administration of ACTH-(1–24). Maintenance of physiological homeostasis of patients with ACTH deficiency corrects not only the levels of cortisol, but also those of aldosterone and DHEA. Intranasal administration of ACTH-(1–24) has the advantage that it corrects the secretion of all three products of the adrenal cortex, offering a novel approach in ACTH substitution therapy.
Acknowledgments
We thank to Dr. R. Walter for his support of this paper.
Footnotes
This work was presented in part at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, 2000.
Abbreviations: DHEA, Dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; in, intranasally.
Received October 26, 2001.
Accepted January 4, 2001.
References
-MSH in humans. Neuroendocrinology 70:63–72[CrossRef][Medline]
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