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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1595-1601
Copyright © 1999 by The Endocrine Society

Original Studies

The Effects of Endogenous Opioids and Cortisol on Thyrotropin and Prolactin Secretion in Patients with Addison’s Disease1

J. Hangaard, M. Andersen, E. Grodum, O. Koldkjær and C. Hagen

Department of Endocrinology (J.H., M.A., E.G., C.H.), Odense University Hospital, DK-5000 Odense C; and Department of Clinical Chemistry (O.K.), Sønderborg Hospital, DK-6400 Sønderborg, Denmark

Address all correspondence and requests for reprints to: Jørgen Hangaard, M.D., Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
This study assessed the controversial role of endogenous opioids and cortisol in the regulation of TSH and PRL secretion in humans. Seven euthyroid male patients with Addison’s disease were studied four times, with an interval of 1–3 months, as follows: 1) during nor-mocortisolism [graduated infusion of hydrocortisone, 0.4 mg/kg, over 19.5 h]; 2) normocortisolism and coadministration of naloxone, at 25 µg/kg·h during the last 6.5 h; 3) hypocortisolism (24 h withdrawal of hydrocortisone, followed by 19.5 h saline infusion); and 4) hypocortisolism plus naloxone administration. The TSH and PRL levels were measured every 15 min, from 0800–1530 h. A TRH test was performed at 1300 h and 1400 h (10 µg and 200 µg of TRH, respectively). The mean TSH level increased significantly during hypocortisolism, compared with normocortisolism (1.78 ± 0.04 vs. 0.84 ± 0.02 mU/L; P < 0.001). The administration of naloxone suppressed the TSH levels during hypo- and normocortisolism (1.78 ± 0.04 vs. 1.50 ± 0.03 and 0.84 ± 0.02 vs. 0.61 ± 0.02 mU/L, respectively; P < 0.001). During hypocortisolism, the TSH responses to small and high doses of TRH were significantly higher than during normocortisolism (P < 0.02). Naloxone had no effect on the TSH responses to TRH, neither during hypo- nor during normocortisolism. The mean PRL level increased significantly during hypocortisolism, compared with normocortisolism (5.8 ± 0.4 vs. 3.6 ± 0.2 µg/L; P < 0.001), and naloxone induced an increase in PRL levels both during hypo- and normocortisolism (7.1 ± 0.7 vs. 4.7 ± 0.5 µg/L, respectively; P < 0.01). The PRL responses to TRH were similar during hypo- and normocortisolism and without any change during opioid receptor blockade. In conclusion, cortisol suppressed basal TSH and PRL secretion and reduced the sensitivity of the thyrotrophs to TRH, without affecting the PRL response to TRH. Our results suggest that endogenous opioids act at the hypothalamic level to stimulate TSH secretion and to suppress the PRL secretion, but these results argue against an essential role of endogenous opioids in the physiological regulation of TSH and PRL secretion in humans.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ENDOCRINE mechanisms subserving an increased TSH and PRL secretion during acute stress (1) and suppressed TSH and PRL levels during more prolonged stress situations are not fully understood. The endogenous opioids have been clearly implicated in the control of secretion of gonadotropins, ACTH, and vasopressin (2, 3, 4, 5); but their role, if any, in controlling TSH and PRL is disputable.

In rats, opioid peptides have an inhibitory influence on TSH secretion, apparently mediated via a decreased TRH release from the hypothalamus (6), although an involvement of opioid receptors, both inside and outside the blood-brain-barrier, has been suggested (7). Human studies, evaluating the effect of exogenous opiates or the effect of the opioid receptor antagonist naloxone, have led to conflicting results, depending on the dose and duration of treatment used in different study designs. The acute administration of opioid peptides may have no effect (8), may inhibit (9), or may increase (2, 10, 11, 12, 13) basal or TRH-stimulated TSH release. Moreover, several studies have found that naloxone, in doses up to 20 mg, had no effect on basal and stimulated TSH secretion (1, 5, 14, 15), whereas other authors have found a decrease in basal TSH secretion (11, 16) or a blunted TSH response to TRH or exogenous opiates (16, 17) in normal subjects.

In a recent study (18), we found a dose-dependent inhibitory action of cortisol on TSH secretion in Addison patients (18). Our results suggested a glucocorticoid-mediated suppression of the pituitary sensitivity to TRH, although a synergistic effect at the hypothalamic level could not be excluded. However, if the endogenous opioids have a stimulatory effect on TSH secretion, the cortisol-induced changes in TSH secretion could be mediated by reciprocal alterations in the hypothalamic release of CRH and ß-endorphin.

Glucocorticoid excess may inhibit PRL gene transcription in the lactotrophs (19), but our recent data suggested that the modulation of PRL secretion during physiological and pathophysiological levels of cortisol was caused by alterations in hypothalamic regulatory mechanisms (18). Although exogenous opioid peptides consistently increase the secretion of PRL (8, 10, 12), conflicting results concerning the effects of naloxone on PRL release have been published. Most studies have reported no effect of naloxone on basal (5, 11, 14, 15, 20), stress-, or exercise-induced (1, 11, 21, 22) and TRH-induced (14, 17) levels of PRL. Some studies have found a naloxone-induced inhibition of PRL release (23). At variance with these findings, an increased basal PRL secretion (4, 5, 24) or an enhanced elevation in exercise- or TRH-induced PRL release (25, 26) has been reported.

The purpose of the present study was to reveal a possible involvement of endogenous opioids in the physiological regulation of TSH and PRL secretion in humans. By use of Addison patients as an in vivo human model, this study was designed to achieve a significant increase in circulating and hypothalamic concentrations of endogenous opioids during hypocortisolism (18, 27, 28, 29). By use of naloxone, to block the effects of endogenously secreted opioids in a placebo-controlled trial, the opioid receptor response to situations with low and increased levels of endogenous opioids, with and without interference from cortisol, was evaluated.


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

Seven male patients (mean age, 46.0 ± 4.8; range, 20–60 yr) with primary adrenocortical insufficiency were studied. Six patients had autoimmune Addison’s disease, and one had adrenocortical insufficiency caused by previous tuberculosis. The patients were carefully selected, i.e. all patients with other endocrine diseases or medications besides substitution therapy had been excluded. Also patients with positive thyroid antibodies were excluded, and all patients were clinically and biochemically euthyroid. Baseline measures of hematological, hepatic, renal, and metabolic functions were normal. Their mean body mass index was 23.9 ± 1.0 kg/m2. All patients were well substituted for several years before study inclusion. The mean duration of disease was 12.3 ± 2.5 yr. The patients received no medication besides their usual substitution therapy of hydrocortisone (HC; median dose, 30 mg/day; range, 20–40 mg/day) and fluohydrocortisone (median dose, 0.05 mg/day; range, 0–0.1 mg/day). The Declaration of Helsinki II was observed, and the study was approved by the local committee on medical ethics. All subjects were volunteers and gave their written consent.

Clinical protocol

All seven patients were investigated on four occasions, in random order, with an interval of 1–3 months: A) normocortisolism and saline placebo infusion; B) normocortisolism and concurrent naloxone-induced opiate receptor blockade; C) hypocortisolism plus saline infusion; and D) hypocortisolism plus naloxone infusion (Fig. 1Go). They were admitted to our stationary clinic the day before blood sampling, and they remained on minimal stress throughout the study period. A cannula was inserted into an antecubital vein in each arm, one for HC/naloxone/saline infusion and one for blood sampling. Saline or HC (0.4 mg/kg·19.5 h) was infused from 2000 h until 1530 h the following day, and the infusion rate was varied during the study period to imitate the normal diurnal rhythm for serum cortisol (between 2000–2400 h: 0.015 mg/kg·h; 2400–0800 h: 0.030 mg/kg·h; 0800–1200 h: 0.024 mg/kg·h; and 1200–1530 h: 0.012 mg/kg·h. In the above: A) In continuation of the conventional HC substitution, HC was infused for 19.5 h; B) Likewise, but from 0900 h until 1530 h, a concomitant infusion of naloxone at 25 µg/kg·h was conducted;. C) After withdrawal of HC, 24 h before admission, the patients had saline infusion for an additional 19.5 h; D) As in C, but between 0900–1530 h, a concomitant infusion of naloxone at 25 µg/kg·h was accomplished.



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  		Figure 1. Study design and time schedule for the investigations during normocortisolism and saline placebo infusion (A), normocortisolism and concurrent naloxone infusion (B), hypocortisolism plus saline placebo infusion (C), and hypocortisolism plus naloxone infusion (D).

 
On all four occasions, a TRH test was performed at 1300 h (10 µg, iv) and at 1400 h (200 µg, iv). During all four occasions, the mineralocorticoid therapy was unchanged. The patients were not fasting, but received a standard meal at 0800 h and 1200 h. To obtain waking baseline levels of PRL, the patients were awake from 0700 h, 1 h before blood sampling.

Blood sampling

After an overnight iv calibration of serum cortisol, blood samples were drawn every 15 min, from 0800–1530 h. TSH was determined every 15 min, PRL was determined every 30 min, ACTH and serum cortisol were determined every hour (from 0800–1500 h plus 1530 h). Serum T4 and T3 were determined at 0800 h, 1200 h, and 1500 h.

Assay

Serum TSH was determined by a Delfia immunofluorometric assay [Wallac, Inc., Turku, Finland; detection limit, 0.01 mU/L; intraassay coefficient of variation (CV), <4.0% for TSH values above 0.5 mU/L and <10.0% for TSH values below 0.5 mU/L]. Serum PRL was determined by Delfia immunofluorometric assay (Wallac; detection limit, 0.02 µg/L; intraassay CV, <4% for PRL values of 2.0–24 µg/L). Serum cortisol was determined by a competitive RIA (Orion Diagnostics, Espoo, Finland); detection limit, 5 nmol/L; intraassay CV, <3%. Plasma ACTH was determined by an immunoradiometric assay (Allegro-IRMA, Nichols Institute Diagnostics, San Juan, Puerto Rico; detection limit, 0.6 pmol/L; intraassay CV, <4%). T4 and T3 were measured by Amerlex-M RIA (Eastman Kodak Co., Rochester, New York; detection limit for T4, 10 nmol/L; detection limit for T3, 0.5 nmol/L; intraassay CV, <2%). To avoid interassay variations, all samples from each individual were analyzed in the same assay.

Data analysis and statistics

The mean TSH and PRL concentrations were calculated using all sampling values from each patient, obtained from 0800–0900 h (prenaloxone) and from 1000–1300 h (naloxone). For statistical calculations, the prenaloxone values and the naloxone periods were compared separately. For ACTH and cortisol, the naloxone period was 1000–1530 h. The groups of related data, during the four different occasions, were analyzed using the Friedman two-way ANOVA. If significant differences were found, the Wilcoxon signed-rank test was used to test differences between paired values. The TSH and PRL responses to TRH (1300–1400 h and 1400–1530 h) were expressed as peak values and maximum increments ({Delta}max). The area under the curve (AUC) for TSH and that for PRL were calculated according to Tai’s model (30). All results are given as the mean ± SE. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Cortisol and ACTH levels

The mean serum cortisol levels during graduated infusion of physiological doses of HC ± naloxone and during saline infusion ± naloxone are shown in Fig. 2aGo. During HC infusion, the mean cortisol concentration declined, from 462 ± 36 nmol/L at 0800 h, to 253 ± 23 nmol/L at 1530 h; and the corresponding levels on the day with concurrent naloxone administration were 483 ± 40 and 258 ± 25 nmol/L, respectively. The mean serum cortisol levels, from 0800–1530 h, were similar on the 2 different days with normocortisolism (355 ± 26 and 362 ± 35 nmol/L, respectively; P > 0.05) and on the 2 days with hypocortisolism (36 ± 4 and 39 ± 4 nmol/L, respectively; P > 0.05). The coadministration of naloxone did not influence the serum cortisol profile. In the time period 1000–1530 h, the mean serum cortisol concentration during normocortisolism and during normocortisolism plus naloxone were 333 ± 32 and 341 ± 37 nmol/L, respectively (P > 0.05). During cortisol withdrawal, the mean cortisol levels were low, stable, and similar on both days and without significant interference from naloxone (P > 0.05).



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  		Figure 2. a, Serum cortisol levels (mean ± SE) in seven Addison patients, during normocortisolism ({blacksquare}); normocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h ({diamondsuit}); hypocortisolism ({square}); and hypocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h ({diamond}). b, Plasma ACTH levels (mean ± SE) in seven Addison patients, during normocortisolism ({blacksquare}); normocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h ({diamondsuit}); hypocortisolism ({square}); and hypocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h ({diamond}).

 
The corresponding mean plasma ACTH values during normo- and hypocortisolism, with and without naloxone infusion, are shown in Fig. 2bGo. On both days with normocortisolism, the mean plasma ACTH levels were within normal range (2–14 pmol/L), and the infusion of naloxone did not induce any significant change in ACTH levels (9.7 ± 2.9 and 10.3 ± 3.0 pmol/L on day A and day B, respectively; P > 0.05). During hypocortisolism, the ACTH levels increased significantly (P < 0.001). Before naloxone infusion (0800–0900 h), the mean ACTH levels were similar on the 2 days (150 ± 29 and 152 ± 38 pmol/L on day C and day D, respectively; P > 0.05), but naloxone infusion induced a significant increase in plasma ACTH levels within 1 h. The mean ACTH level from 1000–1530 h was 132 ± 26 pmol/L during hypocortisolism (day C) and 173 ± 36 pmol/L on the day with coadministration of naloxone (day D); P < 0.001.

Naloxone infusion was not associated with any effect on blood pressure or heart rate, and no side effects were noted.

TSH levels

The basal TSH levels, from 0800–1300 h, during the four study periods A–D, are shown in Fig. 3aGo and Table 1Go. In the time period (0800–0900 h), before naloxone infusion, the TSH mean levels were similar on the 2 different days with normocortisolism (P > 0.05) and similar on the 2 days with hypocortisolism (P > 0.05). Short-term hypocortisolism induced a significant increase in serum TSH levels (P < 0.001). Naloxone infusion decreased the serum level of TSH significantly within 1 h; and between 1000–1300 h, the TSH mean level remained significantly suppressed by naloxone (P < 0.001), both during normocortisolism and during hypocortisolism.



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  		Figure 3. a, Basal TSH levels (mean ± SE) in seven Addison patients, during normocortisolism (A, {blacksquare}); normocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h (B, {diamondsuit}); hypocortisolism (C, {square}); and hypocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h (D, {diamond}). The bars represent TSH mean levels (±SE), from 1000–1300 h on days A, B, C, and D. §, P < 0.001 normocortisolism vs. normocortisolism+naloxone or hypocortisolism vs. hypocortisolism+naloxone; *, P < 0.001 normocortisolism vs. hypocortisolism. b, Basal PRL levels (mean ± SE) in seven Addison patients, during normocortisolism (A, {blacksquare}); normocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h (B, {diamondsuit}); hypocortisolism (C, {square}); and hypocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h (D, {diamond}). The bars represent PRL mean levels (±SE), from 1000–1300 h on days A, B, C, and D. §, P < 0.01 normocortisolism vs. normocortisolism+naloxone or hypocortisolism vs. hypocortisolism+ naloxone. *, P < 0.001 normocortisolism vs. hypocortisolism.

 

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  		Table 1. Basal- and TRH-stimulated TSH data and thyroid hormone levels in seven Addison patients, during normocortisolism, normocortisolism plus naloxone infusion, hypocortisolism, and hypocortisolism plus naloxone infusion

 
The cortisol-mediated inhibition of basal TSH concentration, with and without naloxone administration, was 0.89 ± 0.04 and 0.94 ± 0.02 mU/L, respectively (P > 0.05). The naloxone-mediated inhibition of basal TSH levels was 0.23 ± 0.01 mU/L during low opioid activity (normocortisolism), compared with 0.28 ± 0.03 mU/L during the augmented opioidergic activity induced by hypocortisolism (P > 0.05).

PRL levels

The mean PRL levels, between 0800–1300 h, are shown in Fig. 3bGo and Table 2Go. Before naloxone infusion (0800–0900 h), the PRL levels were similar on the 2 different days with normocortisolism (P > 0.05) and similar on the 2 days with hypocortisolism (P > 0.05). Hypocortisolism induced a significant increase in serum PRL levels (P < 0.001); and during coadministration of naloxone, this increased PRL level was maintained without the diurnal decline in mean PRL level observed during hypocortisolism (P < 0.01). During normocortisolism, the infusion of naloxone induced a similar and significant increase in PRL levels (P < 0.01).


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  		Table 2. Basal- and TRH-stimulated PRL data in seven Addison patients, during normocortisolism, normocortisolism plus naloxone infusion, hypocortisolism, and hypocortisolism plus naloxone infusion.

 
TRH-test

The peak, {Delta}max, and AUC of TSH and PRL responses to low and high doses of TRH are shown in Fig. 4Go, Table 1Go, and Table 2Go. The TSH responses to 10 µg and 200 µg TRH were significantly augmented (P < 0.05) during low cortisol levels, compared with the results obtained during normocortisolism. The changes in {Delta}max of TSH were, however, insignificant during high doses of TRH. Naloxone had no effect (P > 0.05) on any of these response parameters.



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  		Figure 4. a, The TSH response (mean ± SE) to 10 µg TRH at 1300 h and 200 µg TRH at 1400 h, in seven Addison patients, during normocortisolism ({blacksquare}); normocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h ({diamondsuit}); hypocortisolism ({square}); and hypocortisolism+naloxone,25 µg/kg·h, from 0900–1530 h ({diamond}). b, The PRL response (mean ± SE) to 10 µg TRH at 1300 h and 200 µg TRH at 1400 h, in seven Addison patients, during normocortisolism ({blacksquare}); normocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h ({diamondsuit}); hypocortisolism ({square}); and hypocortisolism+naloxone, 25 µg/kg·h, from 0900–1530 h ({diamond}).

 
The PRL responses to 10 µg and 200 µg TRH during hypocortisolism were similar to the responses during normocortisolism (P > 0.05), and they showed no significant change during opioid receptor blockade (P > 0.05).

T4 and T3 levels

The mean serum concentrations of T4 and T3 are shown in Table 1Go. The mean T3 levels increased significantly (1.89 ± 0.10 nmol/L; P < 0.05) during HC withdrawal, compared with 1.74 ± 0.09 nmol/L during normal serum cortisol levels, whereas the mean T4 levels were similar during low and normal serum cortisol levels (85 ± 6 nmol/L vs. 82 ± 9 nmol/L, respectively; P > 0.05). The infusion of naloxone did not induce any significant changes in T4 or T3 levels.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The individual effect of cortisol and opioids on TSH and PRL secretion is difficult to discern in clinical disorders, because many pathophysiological conditions are associated with stress-induced increases in CRH, ß-endorphin, ACTH, and cortisol concentrations (31). In the present study, in Addison patients, we focused on the interplay between cortisol and endogenous opioids to manipulate the endogenous release of opioids, as well as the use of naloxone to block the effects of endogenously secreted opioids. Conflicting data have been obtained using naloxone in different experimental conditions and at different doses. In addition, the effects of naloxone are not always complementary to those of exogenous opiates. Several explanations may account for this discrepancy: exogenous opiates may show pharmacological and not physiological effects; and apparently, some opiates have agonist activity, as well as antagonist activity (13). Furthermore, opiates differ in their relative affinity for different receptor subtypes (13, 32), and the in vivo function of endogenous opioids may involve receptors that are relatively insensitive to naloxone (3, 9, 13, 33, 34, 35). Naloxone is a competitive inhibitor of opiate receptors; but in low doses, it has the highest affinity for µ- and {epsilon}-receptors, whereas relatively large doses are required to block the {delta}- and {kappa}-receptors (3, 33). We have used a constant infusion of medium doses of naloxone without bolus injection to obtain a successive blockade of the opioid receptors.

Opioid peptides are well established as potent inhibitors of the pituitary-adrenal axis in man (1, 2, 5, 36), and their effect seems to be at the hypothalamic level (36, 37, 38). In normal subjects, the infusion of naloxone elevates plasma ACTH and cortisol but only if given in high doses, above 10–15 mg (1, 3, 32, 36, 39, 40). In agreement with these data, we found that the infusion of approximately 9 mg naloxone, over 61/2 h, had no effect on plasma ACTH levels during normocortisolism. During hypocortisolism, however, the plasma ACTH levels were definitely elevated above normal range, and a further significant increase was demonstrated after just 1 h of naloxone infusion (approximately 1.5 mg). These results imply a highly increased endogenous opioid activity during hypocortisolism and a low hypothalamic ß-endorphin activity during the infusion of physiological doses of HC (38).

In accordance with our recent study (18), the present results imply that the cortisol-mediated suppression of TSH is caused, first of all, by a direct pituitary inhibition of TSH secretion. The results obtained during TRH stimulation indicate a cortisol-mediated change in the density of TRH-receptors on the thyrotrophs, which may occur within a few hours (41). Our results do not exclude that this effect may be amplified by an inhibition of TRH release (42, 43), and glucocorticoid-receptors have been demonstrated on all the paraventricular TRH neurons (44). In the present study, serum T3 levels increased significantly during hypocortisolism, and the apparently inappropriate increase in TSH, despite an elevated serum T3 concentration, favor a centrally mediated effect. In accordance with the data of Morley et al. (5), no effect of naloxone on serum T3 or T4 levels was found, neither during hypo- nor eucortisolism.

Our data are consistent with a small, but significant, stimulatory effect of endogenous opioids on basal TSH secretion in humans (11, 45). The naloxone-mediated inhibition of basal TSH secretion was, however, similar during low and augmented opioidergic activity, implying that the endogenous opioids have only minor physiological impact on TSH secretion. This does not exclude, however, a more distinct modulatory impact of opioids during acute stressors with more pronounced increase in hypothalmic opioids.

Some authors have proposed that the effect of endogenous opioids on TSH secretion is mediated at the hypothalamic level (32), although further modulating effects may occur at the pituitary level (46). The human anterior pituitary gland contains high concentrations of metenkephalin (46), and also the in vitro study by Judd et al. (47) indicates that opioid peptides may participate in the regulation of TSH secretion via a direct pituitary action. However, our data strongly suggest that the endogenous opioids act at a suprapituitary site, rather than having a direct pituitary effect, to stimulate TSH secretion. This is in conjunction with the results of Wardlaw et al. (48), who found no stimulatory effect of ß-endorphin in pituitary stalk-sectioned monkeys. Whether this alteration is attributable to an action on endogenous TRH release or other hypothalamic secretagogues is not clear, but an opioid-mediated change in TRH-receptor sensitivity or density seems unlikely, because the pituitary responsiveness to small and high doses of TRH was independent of naloxone infusion. Some experimental data have suggested that endogenous opioids may influence pituitary TSH release, by way of an interaction with opioid receptors on the dopamine nerve terminals, to decrease dopamine release at the median eminence (49, 50). However, because the administration of naloxone increased the secretion of PRL, our data do not support that contention but give evidence for an increased hypothalamic TRH secretion or an interaction with other neurotransmitter systems (12, 21, 51, 52).

Based on our recent (18) and present results, we infer that the modest stimulation of TSH secretion during acute stress may be induced by endogenous opioids secreted in response to endogenous CRH release, whereas the low activity state of the thyrotropic axis, occurring during more prolonged stress (43, 53, 54), may be caused by a cortisol-mediated inhibition of TRH and TSH release.

The increase in serum PRL during hypocortisolism confirms that variations in serum cortisol within the physiological range may modulate PRL secretion (53, 55). It may be brought about by a reduction in the glucocorticoid-mediated suppression of PRL gene transcription (19, 56, 57) or by a change in the sensitivity of the lactotrophs to TRH (58). However, a similar PRL response to TRH, in spite of changes in the glucocorticoid milieu, indicates a hypothalamic site of action (55). An increased hypothalamic ß-endorphin level (59), a ß-endorphin-mediated release of TRH (60), or an increased vasoactive intestinal polypeptide release (61) may be responsible for the enhanced PRL secretion during hypocortisolism. An opioidergic modulation of dopamine secretion is, however, unlikely. If the increased PRL secretion during hypocortisolism was induced by an increased opioid-mediated suppression of dopamine release (49, 50, 62), one would expect a decrement in PRL levels during naloxone infusion. On the contrary, naloxone induced an increase in PRL levels.

Although conflicting results have been obtained by the administration of various doses of naloxone, several authors have claimed that endogenous opioids have a minor stimulatory role or have no effect on PRL release in humans. Our in vivo results provide evidence against a stimulatory effect of endogenous opioids on PRL secretion, and they support the contention that endogenous opioids may have a minor inhibitory influence on basal PRL secretion (24). Because the sensitivity of the lactotrophs to small and high doses of TRH were independent of naloxone administration, a suprapituitary site of action is suggested. The noloxone-induced changes in PRL secretion were, however, similar during low and high opioid activity, which implies that the physiological impact of naloxone-sensitive opioid receptors is of minor importance in the regulation of PRL release in humans. The glucocorticoid modulation of PRL secretion seems to be more pivotal, compared with that of opioid, at least in the doses and time schedule used in this study.

We conclude that cortisol suppresses basal TSH and PRL secretion and reduces the sensitivity of the thyrotrophs to TRH without affecting the PRL response to TRH. Our results imply that endogenous opioids stimulate the TSH release and suggest an increased hypothalamic release of TRH, rather than an inhibition of dopamine secretion. Endogenous opioids had a suppressive effect on PRL secretion, probably mediated at the hypothalamic level, but the physiological role in humans seems minor.


   Footnotes
 
1 This work was supported by grants from the Clinical Research Institute, Odense University Hospital, and the Research Foundation for the Counties of Ribe, Ringkoebing og South Jutland. Back

Received July 1, 1998.

Revised February 1, 1999.

Accepted February 9, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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