leptin and Adrenal-Insufficiency

Studies in animals and humans using supraphysiological doses of dehydroepiandrosterone (DHEA) reported significant changes in body composition and carbohydrate metabolism. To investigate the metabolic action of a physiological DHEA replacement dose, we studied 24 women with adrenal insufficiency (AI; mean +/- SD age, 42.3 +/- 9.3 yr; duration of disease, 9.2 +/- 8.4 yr; body mass index, 23.4 +/- 4.0 kg/m(2)) in a double blind, placebo-controlled, randomized, cross-over design. They received 50 mg DHEA/day and placebo orally for 4 months each, with a 1 -month washout period. Measurements included fasting serum glucose, insulin, leptin, bone markers, anthropometric parameters determined by bioimpedance analysis, and exercise capacity as assessed by an incremental cycling test. DHEA did not induce any change in body mass index (placebo vs. DHEA, 23.3 +/- 4.1 vs. 23.2 +/- 3.9 kg/m(2); P = 0.39), parameters of body composition, or exercise capacity. However, compared with placebo, DHEA replacement led to a significant decrease in serum leptin (absolute change after 4 months, DHEA vs. placebo, -5.3 +/- 8.0 vs. 1.1 +/- 5.7 ng/mL; P = 0.01). This is most likely the result of the DHEA-induced normalization of circulating androgens. DHEA had no effect on fasting glucose, insulin, or the glucose/insulin ratio. Compared with placebo, serum osteocalcin increased slightly, but significantly, during DHEA treatment (absolute change after 4 months DHEA vs. placebo, +1.6 +/- 5.3 vs. -1.2 +/- 6.2 ng/mL; P = 0.02). However, urinary cross-links excretion did not change. In conclusion, replacement of DHEA in a physiological dose in patients with pathological DHEA deficiency does not have a significant effect on carbohydrate metabolism, body composition, or exercise capacity. The biological relevance of the changes in leptin and osteocalcin levels remains to be determined.

Topics: Adrenal Insufficiency; Adult; Body Composition; Bone and Bones; Cross-Over Studies; Dehydroepiandrosterone; Double-Blind Method; Exercise; Female; Hormone Replacement Therapy; Humans; Leptin; Middle Aged

Hypogonadotropic hypogonadism (HH) secondary to hypothalamic gonadotropin-releasing hormone deficiency is a notable feature of a number of rare syndromes, where unlike idiopathic (isolated) HH, other endocrinopathies may also be apparent. The presence of a particular spectrum of clinical features in addition to HH may suggest a particular underlying diagnosis. Placing the diagnosis of HH into that context will then have important implications in terms of management and predicting long-term functional outcome. In some instances, establishing the genetic basis of a particular syndrome or disorder has advanced the understanding of normal hypothalamo-pituitary-gonadal function (e.g. LEP deficiency, DAX-1 and CHARGE syndrome) whilst in other disorders much has still to be learnt (e.g. Bardet-Biedl and Prader-Willi syndrome). In this chapter the above syndromes, where HH is a feature in most or all affected individuals, will be discussed. Recent advances in our understanding of the pathophysiology of the HH will be highlighted and management options presented. Longer term therapy with sex steroid replacement is becoming even more important if improvements in life expectancy are to be matched by improvements in quality of life.

Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Animals; Bardet-Biedl Syndrome; CHARGE Syndrome; DAX-1 Orphan Nuclear Receptor; Female; Genetic Diseases, X-Linked; Hormone Replacement Therapy; Humans; Hypoadrenocorticism, Familial; Hypogonadism; Leptin; Male; Mice; Prader-Willi Syndrome; Proprotein Convertase 1

In diabetes, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis causes effects such as elevation of corticotropin (ACTH) and glucocorticoids. Cholecystokinin and its receptors are involved in the HPA axis and influence the regulation of the HPA axis. We examined adrenocortical function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, that lack the cholecystokinin A receptor. We measured adrenal weight, plasma ACTH, serum and urinary corticosterone, and serum leptin in OLETF rats at 5 to 36 weeks of age. Messenger RNA (mRNA) expression of 11beta-hydroxysteroid dehydrogenase and 5alpha-reductase type 1 in adrenal glands of the rats were examined. Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In OLETF rats at 32 to 36 weeks of age, plasma ACTH was significantly higher (P < .001); serum corticosterone and 24-hour urinary corticosterone were significantly lower (P < .005); and adrenal weight was significantly lower (P < .005) than those in LETO rats. At the same ages, serum leptin in OLETF rats was significantly higher (P < .001) than that in LETO rats. In the younger OLETF rats, these changes were not observed. Overall, there was an inverse correlation between serum corticosterone and serum leptin (r = -0.374, P < .0005), whereas there was a positive correlation between plasma ACTH and serum leptin (r = 0.654, P < .0001). At 5 and 36 weeks of age, mRNA expression of 5alpha-reductase type 1 in the adrenal gland of OLETF rats was significantly higher (P < .05) than that of LETO rats, whereas there was no significant difference in mRNA expressions of 11beta-hydroxysteroid dehydrogenase types 1 and 2. We showed that adrenocortical insufficiency and adrenal atrophy were acquired in OLETF rats, and the possibility of elevated serum leptin relates to this phenomenon.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adrenal Cortex; Adrenal Cortex Function Tests; Adrenal Glands; Adrenal Insufficiency; Adrenocorticotropic Hormone; Aging; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; DNA Primers; Insulin; Leptin; Organ Size; Rats; Rats, Inbred OLETF; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The present study was designed to examine the hypothesis that hypothalamic-pituitary-adrenal axis activity as measured by 24-h cortisol production rate (CPR) and plasma levels of free cortisol is linked to increased body fat in adults, and that increased cortisol levels with aging results from increased CPR. Fifty-four healthy men and women volunteers with a wide range of body mass indexes and ages underwent measurement of CPR by isotope dilution measured by gas chromatography-mass spectroscopy, cortisol-binding globulin, and free cortisol in pooled 24-h plasma, body composition, and leptin. Cortisol clearance rates were determined from the 10-h disappearance curves of hydrocortisone after steady-state infusion in a separate group of lean and obese subjects with adrenal insufficiency. Although CPR significantly increased with increasing body mass index and percentage body fat, free cortisol levels remained independent of body composition and leptin levels due to increased cortisol clearance rates. CPR and free cortisol levels were, however, significantly higher in men than women. In addition, 24-h plasma free cortisol levels were increased with age in association with increased CPR, independent of body size. This increase in hypothalamic-pituitary-adrenal axis activity may play a role in the alterations in body composition and central fat distribution in men vs. women and with aging.

Topics: Adrenal Insufficiency; Adult; Aged; Aging; Body Composition; Carrier Proteins; Circadian Rhythm; Female; Humans; Hydrocortisone; Indicator Dilution Techniques; Leptin; Male; Menopause; Metabolic Clearance Rate; Middle Aged; Obesity; Sex Characteristics

Topics: Adrenal Cortex; Adrenal Insufficiency; Humans; Hydrocortisone; Leptin; Lipodystrophy; Pituitary-Adrenal System

Levels of leptin throughout the day follow a circadian pattern, with a trough in the late morning/early afternoon and a peak at midnight. This pattern of appearance of leptin correlates inversely with the circadian appearance of cortisol. Pharmacological doses of cortisol increase leptin messenger RNA expression in vitro and raise plasma leptin levels in animals and humans. To determine whether the circadian appearance of leptin might be accounted for by delayed effects from physiological cortisol secretion on fat cells, seven subjects with confirmed adrenal failure were admitted to the Clinical Research Center, on three separate dates, to receive 48-h infusions of: continuous normal saline (NS), a normal daily amount and diurnal pattern of cortisol (ND), and a normal daily amount but reversed diurnal pattern of cortisol. Blood samples were taken every 15 min during the second 24 h of infusion and pooled for hourly measurements of leptin. The circadian pattern of leptin appearance was unchanged during all of the infusion protocols. Area-under-the-curve analysis showed no differences in the total amount of leptin during the NS and ND protocols (20,565 ng/mL x 24 h vs. 20,637 ng/mL x 24 h during NS and ND protocols, respectively; P = 0.94). Acute changes in physiological levels of cortisol do not affect the circadian appearance of leptin in subjects with adrenal failure, nor is cortisol required to maintain normal leptin levels for up to 72 h. The circadian variation of leptin levels cannot be accounted for by normal activity of the hypothalamic-pituitary-adrenal axis.

Topics: Adrenal Insufficiency; Adult; Aged; Circadian Rhythm; Female; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Proteins