CRH Stimulation Research Articles

Responses of the LHPA-system to CRH stimulation in subjects with type 1 diabetes mellitus and obesity

Responses of the LHPA-system to CRH stimulation in subjects with type 1 diabetes mellitus and obesity

An Assessment of Petrosal Sinus Sampling for Localization of Pituitary Microadenomas in Children with Cushing Disease

Pituitary adenomas in Cushing disease (CD) are usually small and difficult to visualize. Bilateral inferior petrosal venous sampling (BIPSS) before and after ovine CRH stimulation is reserved for patients who have ACTH-dependent Cushing syndrome and negative magnetic resonance imaging (MRI) or positive MRI but inconsistent biochemical data. The objective of the study was to evaluate the usefulness of BIPSS as a tool for localization of a pituitary adenoma in children with CD. The study was a retrospective review of the records of 141 children who were admitted for evaluation of CD from 1982 to 2004. The study was conducted at a tertiary care center. Lateralization of ACTH secretion during BIPSS was compared with MRI and surgical findings for the localization of a microadenoma. A total of 94 patients, 49 males and 45 females with an age range of 5.3 to 18.7 yr (13 +/- 3.2 yr), underwent BIPSS. Localization of a microadenoma by BIPSS agreed with surgical location in only 58% of the cases (95% confidence interval, 43-66). The combined use of information from the MRI and inferior petrosal venous sampling did not predict the location of the tumor more frequently than MRI alone (P > 0.1), which in this study localized a lesion in 39% of the patients (95% confidence interval, 28-50). The procedure was completed successfully in all patients, and no serious complications were recorded. Although BIPSS was safe and well tolerated in an experienced center, lateralization of the ACTH gradient during BIPSS was a poor predictor of the site of the adenoma in children with CD.

Cushing’s Syndrome Due to Ectopic Corticotropin Secretion: Twenty Years’ Experience at the National Institutes of Health

Ectopic ACTH secretion (EAS) is difficult to diagnose and treat. We present our experience with EAS from 1983 to 2004. The study was performed at a tertiary care clinical research center. Ninety patients, aged 8-72 yr, including 48 females were included in the study. Tests included 8 mg dexamethasone suppression, CRH stimulation, inferior petrosal sinus sampling (IPSS), computed tomography, octreotide scan, magnetic resonance imaging, and/or venous sampling. Therapies, pathological examinations, and survival were noted. Eighty-six to 94% of patients did not respond to CRH or dexamethasone suppression, whereas 66 of 67 had negative IPSS. To control hypercortisolism, 62 patients received medical treatment, and 33 had bilateral adrenalectomy. Imaging localized tumors in 67 of 90 patients. Surgery confirmed an ACTH-secreting tumor in 59 of 66 patients and cured 65%. Nonthymic carcinoids took longest to localize. Deaths included three of 35 with pulmonary carcinoid, two of five with thymic carcinoid, four of six with gastrinoma, two of 13 with neuroendocrine tumor, two of two with medullary thyroid cancer, one of five with pheochromocytoma, three of three with small-cell lung cancer, and two of 17 with occult tumor. Patients with other carcinoids and ethesioneuroblastoma are alive. IPSS best identifies EAS. Initial failed localization is common and suggests pulmonary carcinoid. Although only 47% achieved cure, survival is good except in patients with small-cell lung cancer, medullary thyroid cancer, and gastrinoma.

Sex-Related Differences in Stimulated Hypothalamic-Pituitary-Adrenal Axis during Induced Gonadal Suppression

Sex-related differences in the stress response are well described in the animal literature but in humans are inconsistent and appear to reflect both the method used to stimulate the hypothalamic-pituitary-adrenal (HPA) axis and the age of the subjects. Sex-related differences in reproductive steroid levels further confound efforts to define the specific role of the sex of the individual in stress axis responsivity. The aim of this study was to address this role independent of differences in reproductive steroid levels. We compared HPA axis response to pharmacological (CRH) and physiological (exercise) stressors in two groups of young to middle-aged (18-45 yr) men (n = 10 and 8) and women (n = 12 and 13) undergoing gonadal suppression with leuprolide acetate (monthly im injection of 7.5 mg in men and 3.75 mg in women). Exercise and CRH stimulation tests were performed during induced hypogonadal conditions. The study was conducted at a National Institutes of Health Clinical Center Outpatient Clinic. PATIENT OR OTHER PARTICIPANTS: Male and female normal volunteers participated in the study. The main outcome measures were stimulated ACTH and cortisol levels. Both CRH (1 microg/kg) stimulation and graded treadmill exercise stimulation occurred in the month after the second leuprolide injection to ensure gonadal suppression. Despite the absence of sex differences in estradiol or testosterone at the time of testing, men showed increased stimulated ACTH (repeated-measures ANOVA for CRH, P < 0.005) and cortisol (repeated-measures ANOVA for exercise, P < 0.05) compared with women. Among the summary measures, area under the curve (AUC) for cortisol was significantly greater in men than women after exercise. Although the AUC for ACTH was not significantly different across sexes, the initial AUC (0-30 min) was significantly greater in men for both procedures. No significant sex differences were found in a measure of adrenal responsivity, the cortisol to ACTH ratio, for either procedure. Cortisol-binding globulin levels did not differ between men and women and were not correlated with stimulated HPA axis measures. These data confirm earlier reports of sex differences in stimulated HPA axis activity and demonstrate that these differences exist even under induced hypogonadal conditions (i.e. in the absence of characteristic differences in reproductive steroids).

Testosterone Suppression of CRH-Stimulated Cortisol in Men

Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in 10 men (ages 18-45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p<0.05, 0.005, and 0.01, respectively) during testosterone replacement compared with the induced hypogonadal condition (leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p<0.1). Paradoxically, CRH-stimulated corticotropin (ACTH) was increased significantly during testosterone replacement (p<0.05). The cortisol : ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p<0.1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.

The Hypothalamic-Pituitary-Adrenal Axis in Pregnancy: Challenges in Disease Detection and Treatment

Pregnancy dramatically affects the hypothalamic-pituitary-adrenal axis leading to increased circulating cortisol and ACTH levels during gestation, reaching values in the range seen in Cushing's syndrome (CS). The cause(s) of increased ACTH may include placental synthesis and release of biologically active CRH and ACTH, pituitary desensitization to cortisol feedback, or enhanced pituitary responses to corticotropin-releasing factors. In this context, challenges in diagnosis and management of disorders of the hypothalamic-pituitary-adrenal axis in pregnancy are discussed. CS in pregnancy is uncommon and is associated with fetal morbidity and mortality. The diagnosis may be missed because of overlapping clinical and biochemical features in pregnancy. The proportion of patients with primary adrenal causes of CS is increased in pregnancy. CRH stimulation testing and inferior petrosal sinus sampling can identify patients with Cushing's disease. Surgery is a safe option for treatment in the second trimester; otherwise medical therapy may be used. Women with known adrenal insufficiency that is appropriately treated can expect to have uneventful pregnancies. Whereas a fetal/placental source of cortisol may mitigate crisis during gestation, unrecognized adrenal insufficiency may lead to maternal or fetal demise either during gestation or in the puerperium. Appropriate treatment and management of labor are reviewed.

Immeasurably Low and Non-TRH-stimulatable TSH Associated with Normal I-123 Uptake in Two Goitrous Euthyroid Patients: Possible Existence of Other Thyroid-hormone Regulated Thyroid Stimulators other than TSH

We described two euthyroid patients with normally functioning goiters, but with persistently undetectable and non-stimulatable TSH levels. Subject 1 was a 64-year-old woman with a large diffuse goiter who has been clinically and biochemically euthyroid without any medication for at least 19 years. Subject 2 was a 31-year-old woman with a small diffuse goiter who has been euthyroid for 4 years. Both patients had persistently undetectable levels of serum TSH, TSH receptor antibodies (TRAb) and thyroid stimulating antibodies (TSAb). Their basal TSH levels were very low and their T3 responses to TRH were very diminished or absent. In contrast, the basal levels of the other pituitary hormones and their responses to LHRH, GRH and CRH stimulation were all within normal limits in both patients. MRI images of pituitary glands, 123I thyroid uptake, and thyroid scans were normal. Ectopic thyroids were not detected on (99m)TcO4- and 123I total body scans. Factors interfering with the measurement of TSH were excluded by recovery studies. In subject 1 a T3-suppression test was positive and a perchlorate discharge test was negative. In subject 2 a T3-suppression test was negative. Euthyroid Graves' disease, subclinical hyperthyroidism, destructive thyroiditis, thyrotoxicosis of extrathyroid origin, central hypothyroidism, and nonthyroidal illness were all ruled out by these observations. These results suggest that an unknown factor, such as thyrostimulin, but not TSH or TSAb, stimulates the thyroid and maintains euthyroidism, and may have a role in the regulation of the hypothalamus-pituitary-thyroid axis.

Olfactory Neuroblastoma Causing Ectopic ACTH Syndrome

A 39-year-old woman who presented with typical Cushingoid appearance (moon facies, central obesity, purpura) was admitted to our hospital because of pulmonary infection. She was found to have hypertension, severe hypokalemia, and metabolic alkalosis. Endocrine data revealed elevated plasma levels of ACTH and cortisol with lack of circadian rhythm, non-suppressibility to high-dose dexamethasone, and hyperresponsiveness to CRH stimulation. Although no pituitary mass was detected by MRI of the brain, inferior petrosal sinus sampling showed a step-up of central to peripheral ACTH levels; these data are consistent with the diagnosis of Cushing's disease. She was successfully treated with metyrapone to control hypercortisolemia. Ten months later, a mass was detected in the ethmoid sinus, which was surgically removed. After resection of the ethmoid sinus tumor, her Cushingoid features and hypercortisolemia disappeared, but recurred after enlargement of a second mass in the maxillary sinus. After resection of the maxillary sinus tumor, her hypercortisolemia subsided. Histologically, the tumor tissues from both the ethmoid and maxillary sinus were identical and consistent with the diagnosis of olfactory neuroblastoma. Immunohistochemically, the immunoreactivities of ACTH and POMC were positive in the cytoplasm of tumor cells, and immunoreactive ACTH was demonstrated in both tumor tissues. Thus, this is the second rare case with ectopic ACTH syndrome caused by olfactory neuroblastoma thus far reported.

Effect of Pioglitazone on Adrenocorticotropic Hormone and Cortisol Secretion in Cushing’s Disease

The lack of an effective medical therapy for patients with Cushing's disease (CD) requires the search for new modalities of treatment. Peroxisomal proliferator-activated receptors (PPAR)-gamma are abundantly expressed in ACTH-secreting pituitary tumors. Treatment with PPARgamma agonists inhibits ACTH-secreting pituitary tumor growth, proliferation, and ACTH secretion in vitro in human and murine models and in vivo in murine corticotroph tumors. It was hypothesized that treatment with the PPARgamma agonist pioglitazone would normalize the hypothalamic-pituitary-adrenal axis of patients with CD. We evaluated the hypothalamic pituitary adrenal axis in five patients with CD in whom we measured: 1) the 24-h urine concentration of free cortisol; 2) the 24-h profile of serum cortisol and plasma ACTH; and 3) the ACTH and cortisol response to CRH stimulation. All measurements were taken at baseline and after low-dose dexamethasone treatment (0.5 mg dexamethasone every 6 h). The entire protocol was done before and after 30 d of treatment with 45 mg of daily oral pioglitazone. At baseline, before low-dose dexamethasone, all five patients had elevated 24-h urine free cortisol, elevated 24-h serum cortisol and plasma ACTH levels, and robust responses to CRH, consistent with their diagnosis of CD. There was no significant change in any of the above variables after 30 d of treatment with pioglitazone. Furthermore, there was no significant difference in the number of cortisol or ACTH spikes or in their diurnal rhythms. In summary, pioglitazone treatment (45 mg daily for 30 d) of patients with CD was not found to be effective at attenuating either ACTH or cortisol levels and does not appear to be an alternative to surgical therapy.

Cortisol Response to Ovine Corticotropin-Releasing Hormone in a Model of Pregnancy and Parturition in Euthymic Women with and without a History of Postpartum Depression

Hypothalamic-pituitary-adrenal axis abnormalities have been reported in depressed women and those with postpartum blues, compared with nondepressed women. We investigated the effect of gonadal steroids on the hormonal response to ovine CRH in women with (n = 5) and without (n = 7) a past history of postpartum depression (PPD) by creating an endocrine model of pregnancy and the postpartum. Ovine CRH (1 microg/kg) stimulation tests were performed in the baseline follicular phase, during hormone add-back (leuprolide acetate plus supraphysiologic doses of estradiol and progesterone-mimicking pregnancy), and after precipitous withdrawal of hormone replacement (mimicking the puerperium). Significant phase by time (P < 0.005) and phase by diagnosis (P < 0.05) interactions were observed, reflecting increased stimulated cortisol during the supraphysiologic phase, particularly in subjects with a history of PPD. Cortisol area under the curve also showed a significant phase by diagnosis effect (P < 0.05). Significant increases during the supraphysiologic phase were also seen for urinary free cortisol (P < 0.05), cortisol area under the curve (P < 0.001), and plasma corticosteroid-binding globulin (P < 0.05). Our data show that in humans, as in animals, supraphysiologic gonadal steroid levels enhance pituitary-adrenal axis activity, and, further, that women with a history of PPD have an enhanced sensitivity of the pituitary-adrenal axis to gonadal steroids.

Diagnostic errors after inferior petrosal sinus sampling.

Although inferior petrosal sinus sampling (IPSS) is useful in the evaluation of Cushing's syndrome, false negative cases have been described, and many patients presumed to have ectopic tumors based upon negative IPSS remain without a final diagnosis. These patients are often managed as if they have as yet undiscovered ectopic tumors. To test this assumption, we conducted a retrospective review of our results to determine the ultimate diagnoses after IPSS. Between 1986 and 2002, 179 patients underwent 185 IPSS procedures as part of their evaluation for Cushing's syndrome. Confirmed diagnoses were available for 149 patients (83%): 139 patients had pituitary adenomas (94%), eight had bronchial carcinoids (5%), and two had adrenal tumors (1%). Threshold criteria for a pituitary source were defined as an inferior petrosal sinus to peripheral (IPS:P) basal ratio of 2:1 or greater without CRH or an IPS:P ratio of 3:1 or greater after CRH stimulation. There were nine patients in whom the IPS:P ratio failed to meet threshold criteria after successful sampling, but were nonetheless found to have pituitary tumors after transsphenoidal exploration (false negatives). Eight of these had received CRH and had a significant rise (>35%) in peripheral ACTH levels after CRH treatment, even though the IPS:P ratio did not reach the threshold. There were two patients in whom the IPS:P ratio reached threshold criteria, and ectopic tumors were demonstrated as the source of ACTH overproduction (false positives). The sensitivity after CRH stimulation was 90% (95% confidence interval, 80.8-95.5%) with a specificity of 67% (95% confidence interval, 11.4-94.5%). The positive and negative predictive values were 99 and 20%, respectively. Our data show that patients with an IPS:P ratio suggestive of a nonpituitary source of ACTH overproduction may still have Cushing's disease. Analyzing the CRH-stimulated peripheral ACTH levels in addition to the standard IPS:P ratios may provide improved diagnostic accuracy. Transsphenoidal exploration should be considered in all cases of unsuccessful sampling and in those cases for which no ectopic source can be identified after further body imaging, even if the IPSS is negative, and especially if peripheral ACTH levels rise significantly with CRH stimulation.

Endocrinologic and psychologic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stress.

Carriers of congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency demonstrate increased secretion of cortisol precursors after ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic CRH secretion. Because both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression, we performed endocrine and psychologic studies in consecutively admitted parents of patients with classic congenital adrenal hyperplasia due to 21-OH deficiency and parents of children with other chronic endocrine disorders. The number of excluded carriers because of pathologic reasons was higher than that of controls (P = 0.05). Carriers of 21-OH deficiency had a lower mean 24-h urinary free cortisol excretion (26.4 +/- 3.4 vs. 42.7 +/- 6.4 microg/d, P = 0.03) and higher peak ACTH (75.7 +/- 8.1 vs. 54.2 +/- 5.9 pg/ml, P = 0.04) and 17-hydroxyprogesterone (224.2 +/- 28.1 vs. 107.1 +/- 12.5 ng/dl, P < 0.001) concentrations post CRH stimulation than control subjects. Cortisol and androstenedione responses were similar in the two groups. Psychometric assessment performed by administering the State-Anxiety Inventory, Beck Depression Inventory, Profile of Mood States, Symptom Checklist-90R, and Temperament and Character Inventory revealed no differences between the two subject groups. Interestingly, a stepwise multiple linear regression model analysis in each population sample revealed that in carriers of 21-OH deficiency but not in the control subjects, a lower mean 24-h urinary free cortisol excretion and a higher ACTH response to ovine CRH stimulation predicted predisposition to obsessive-compulsive behavior, novelty seeking, reward dependence, and harm avoidance. We conclude that carriers of 21-OH deficiency appear to have mild hypocortisolism and compensatory changes of CRH secretion secondary to lower cortisol concentrations. These changes might predict mild predisposition of these subjects to physical and psychologic pathology, suggesting that larger studies are necessary.

Baseline and CRH-stimulated ACTH and cortisol levels after administration of the peroxisome proliferator-activated receptor-γ ligand, rosiglitazone, in Cushing’s disease

The ability of acute rosiglitazone administration in influencing ACTH/cortisol secretion in basal conditions and after CRH stimulation was studied in patients with Cushing's disease. Ten patients (8 women and 2 men, aged 18-65 yr) with Cushing's disease were enrolled in the study: 6 of them had previously undergone unsuccessful surgery and 4 were untreated. Plasma ACTH and serum cortisol levels were evaluated at serial time points for 3 h during saline infusion and after the administration of rosiglitazone (8 mg, po) and for 1 h after the injection of CRH (1 microg/kg iv) given alone or 30 min following rosiglitazone administration. The 4 tests were performed in all subjects in randomized order on different days. No significant difference was observed between the pattern of hormone secretion during saline alone and after rosiglitazone, as evaluated by two-way analysis of variance (ANOVA). The integrated areas under the curves (AUCs) were also not significantly different (ACTH: 5683 +/- 1038 vs 6111 +/- 1007 pg/ml/180 min; cortisol: 2333 +/- 267 vs 2902 +/- 486 microg/dl/180 min). In addition, there was no difference for ACTH and cortisol responses to CRH given either alone or after rosiglitazone, when evaluated as peak, increment or AUC; the pattern of the responses analyzed by two-way ANOVA was also similar. 1) the administration of a single dose of rosiglitazone did not decrease ACTH/cortisol levels or blunt their response after CRH injection; 2) the activation of PPAR-gamma receptors by rosiglitazone seems unable to affect ACTH and cortisol secretion, at least in acute conditions, in patients with ACTH-secreting pituitary adenomas.

Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis: low birth weight and central HPA regulation.

Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an intermediary in the association between reduced fetal growth and adult cardiovascular and metabolic diseases. Previous studies have shown that small size at birth is associated with increased fasting plasma cortisol and adrenal responsiveness to ACTH stimulation. We have extended these studies by evaluating the salivary cortisol response to awakening and plasma ACTH and cortisol responses to CRH stimulation and a dexamethasone-suppressed CRH (DEX/CRH) test in a group of low birth weight [LBW; <3.18 kg (7 lb), n = 58] and high birth weight [>3.86 kg (8.5 lb), n = 65] men aged 60-69 yr. Despite no difference in basal pituitary-adrenal activity or in their ACTH and cortisol responses to CRH, LBW men had significantly lower pituitary-adrenal responses in the DEX/CRH test. Although these findings do not explain the HPA abnormalities associated with LBW in previous studies, they provide further evidence of dysregulation of the HPA axis in people who were small at birth.

Hypophyseal coma

Pituitary coma is a rare case of emergency and primarily due to ACTH and TSH deficiency. Pituitary coma occurs more often in patients with well-known pituitary deficiency than in patients with intrasellar tumor. Clinical manifestations are hypotonia, bradycardia, decreased skin and nipple pigmentation, muscle weakness, vomitus, nausea, obstipation, hypothermia, and hypoventilation. A postpartal agalactia is often the first sign of Sheehan's syndrome. Unlike primary adrenal insufficiency (Addison's disease) ACTH deficiency does not cause hyperpigmentation, hyperkalemia, or salt loss. The suspicion of pituitary coma requires replacement with 100 mg hydrocortisone iv, 200 mg hydrocortisone iv/24 h, 500 micro g levothyroxine iv and fluid substitution. Since thyroxine accelerates the degradation of cortisol and can precipitate adrenal crisis in patients with limited pituitary reserve, hydrocortisone replacement should always precede levothyroxine therapy. ACTH stimulation test, CRH stimulation test and insulin tolerance test (optional) should be performed after therapeutic compensation to determine pituitary function.

Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects

A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system has been hypothesized to account for a myriad of cardinal symptoms of affective disorders. Specifically, increased CRH signalling via CRH type 1 receptors is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of drugs have been developed in order to target the postulated increase in CRH/CRH 1 receptor signalling. One of these compounds, R121919, binds with high affinity to CRH1 receptors antagonising the action of CRH. R121919 was recently tested in an open-label study conceptualized as a safety and tolerability study. As part of this study, a thorough endocrine evaluation and detailed clinical laboratory analysis were assessed several times during 30 days of treatment with two different dose regimens of R121919 (5–40 mg vs. 40–80 mg) in 24 patients with a major depressive episode. During treatment with the experimental drug no serious side effects were noted. In particular, there were no adverse effects or impairment of the hypothalamic–pituitary–gonadal system, the hypothalamic–pituitary–thyroid axis, the renin–angiotensin system, prolactin or vasopressin secretion. Furthermore, no changes in the serum corticotropin and cortisol concentrations and in the responsivity of corticotropin and cortisol following a CRH stimulation test were noted. No effects of R121919 on clinical laboratory parameters including liver enzymes, EEG and ECG were observed. These results encourage the development of other CRH-1-R antagonists as a novel class of antidepressive drugs.

Hypothalamo-pituitary-adrenal function in patients with depressive disorders is correlated with baseline cytokine levels, but not with cytokine responses to hydrocortisone

Dysfunction of the hyopthalamo-pituitary adrenal (HPA) system is frequently found in major depression. In addition, signs of non-specific inflammatory system activation have been reported. However, very little is known about interactions between the HPA and immune systems in depressive patients. To assess HPA system function, we performed a combined dexamethasone suppression and corticotropin-releasing hormone stimulation (DEX/CRH) test in 14 depressive patients. Moreover, baseline nocturnal plasma levels of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α were measured. In addition, the system was challenged with an intraveneous pulsatile injection of hydrocortisone (1 mg/kg body weight in total) and again cytokine levels were measured across one night. Baseline TNF-α levels were negatively correlated with the amount of ACTH released upon CRH stimulation during the DEX/CRH test. Acute hydrocortisone administration suppressed TNF-α and IL-6 levels independently of baseline HPA system activity. We conclude that chronic HPA system overactivity in depressed patients might compromise the production of inflammatory cytokines under baseline conditions. However, the responsivity of the cytokine production to acutely administered glucocorticoids does not seem to correlate with the state of the HPA system.

Lithium Augmentation Increases the ACTH and Cortisol Response in the Combined DEX/CRH Test in Unipolar Major Depression

Lithium augmentation is a well established strategy for treatment-resistant depression. The exact mode of its action is unknown, but an enhancement of serotonergic transmission is hypothesized. The authors investigated changes in the hypothalamic-pituitary-adrenocortical (HPA) system during lithium augmentation and their correlation to clinical response by means of the combined dexamethasone/CRH test (DEX/CRH test). Thirty patients with unipolar major depressive episodes (DSM IV) who had not responded to an adequate trial with an antidepressant were assessed on the day before lithium augmentation (baseline) with the DEX/CRH test (pretreatment with 1.5 mg dexamethasone p.o. at 11 p.m. and CRH stimulation at 3 p.m. on the next day). Twenty-four patients were re-assessed after response was determined or, in cases of non-response, four weeks after initiation of lithium augmentation. Response to lithium augmentation was measured by weekly ratings on the Hamilton Depression Rating Scale (HDRS 17-item version). Response was defined as a ΔHDRS of ⩾50% and an endpoint score of < 10. Patients had a significantly higher ACTH and cortisol response to CRH stimulation during lithium augmentation compared with the values at baseline. There was no difference in ACTH and cortisol reaction between responders and non-responders to lithium augmentation. This increase is in contrast to the known normalization of HPA-axis overdrive after treatment with a tricyclic antidepressant like amitriptyline. Because the effect was independent of response status we suggest that this increase reflects an effect of lithium that is independent from the psychopathological state or its change. This effect might be explained by the serotonergic effects of lithium.

Effect of Leptin Replacement on Pituitary Hormone Regulation in Patients with Severe Lipodystrophy

Leptin is important in regulating energy homeostasis. Severe lipodystrophy is associated with leptin deficiency and insulin resistance, hypertriglyceridemia, and hepatic steatosis. Leptin deficiency is also associated with abnormalities of the pituitary hormones in rodent models and patients with congenital absence of leptin. We inquired whether similar abnormalities are seen in patients with lipodystrophy and whether replacement of leptin will make an impact on the regulation of pituitary hormones. Seven female patients (aged 15-42 yr, all diabetic) with lipodystrophy and serum leptin levels less than 4 mg/liter were treated with recombinant methionyl-human leptin (recombinant leptin) in physiological doses in an open-labeled study. The following parameters were evaluated before and at 4 months of leptin treatment: menstrual history, pelvic ultrasonogram, LHRH, TRH, and CRH tests. While on recombinant leptin, mean serum leptin concentration increased from 1.3 +/- 0.3 mg/liter to 11.1 +/- 2.5 mg/liter. Only one of five patients who had intact reproductive systems was cycling normally before leptin therapy, and all five had normal menses by the fourth month of leptin therapy. Serum E2 concentrations increased (110 +/- 44 pmol/liter vs. 546 +/- 247 pmol/liter, P = 0.002), serum T concentrations decreased (3.5 +/- 3.0 nmol/liter vs. 1.3 +/- 0.7 nmol/liter, P = 0.055), and the attenuated LH response to LHRH was corrected with therapy. Serum T(3) and free T(4) were in the normal range before leptin therapy and did not change. However, serum TSH concentrations fell from 2.2 +/- 1.1 microU/ml to 1.2 +/- 0.7 microU/ml (P < 0.001). The percent increase in TSH following TRH administration was similar before (560%) and at 4 months (580%) of leptin therapy. The mean nonstimulated ACTH and cortisol concentrations were, respectively, 6.0 +/- 3.4 pmol/liter and 680 +/- 280 nmol/liter before leptin and did not change after 4 months of therapy (4.2 +/- 1.2 pmol/liter, P = 0.11 and 453 +/- 142 nmol/liter, P = 0.13, respectively). The ACTH and cortisol responses to CRH stimulation were normal both before and after therapy. Leptin replacement improved menstrual abnormalities and low E2 levels and corrected the attenuated LH response to LHRH in a group of young women with lipodystrophy and leptin deficiency. These results add to the growing body of evidence that metabolic signals such as leptin play a role in neuroendocrine regulation.

Hypothalamic-pituitary-adrenal axis function and cytokine production in multiple sclerosis with or without interferon-beta treatment.

Pro-inflammatory cytokines mediate brain damage in multiple sclerosis (MS); they can also influence the hypothalamic-pituitary-adrenal (HPA) axis function. We evaluated the possible abnormalities of HPA axis function in relapsing-remitting MS (RR-MS). IFN-gamma, TNF-alpha and IL-6 production by ex-vivo lymphocytes from 10 normal volunteers and 10 RR-MS patients before and during IFN-beta therapy was assessed; pituitary-adrenal function was evaluated by means of CRH and ACTH stimulation tests. In untreated patients the production of IFN-gamma, TNF-alpha, IL-6 was increased, and was significantly decreased by IFN-beta. Neither basal, nor stimulated ACTH, cortisol, DHEA, DHEAs, 17-alpha-OH-progesterone levels differed between controls and RR-MS patients, both before and during treatment. Moreover, no correlation was found between endocrine and immune parameters. In MS the HPA axis function seems normal and not influenced by IFN-beta treatment. This result is discussed in relation to the increased production of pro-inflammatory cytokines found in this disease.