Effects of ghrelin administration on decreased growth hormone status in obese animals

Obesity is characterized by markedly decreased ghrelin and growth hormone (GH) secretion. Ghrelin is a GH-stimulating, stomach-derived peptide that also has orexigenic action. Ghrelin supplement may restore decreased GH secretion in obesity, but it may worsen obesity by its orexigenic action. To reveal effects of ghrelin administration on obese animals, we first examined acute GH and orexigenic responses to ghrelin in three different obese and/or diabetic mouse models: db/db mice, mice on a high-fat diet (HFD mice), and Akita mice for comparison. GH responses to ghrelin were significantly suppressed in db/db, HFD, and Akita mice. Food intake of db/db and Akita mice were basally higher, and further stimulation of food intake by ghrelin was suppressed. Pituitary GH secretagogue receptor mRNA levels in db/db and HFD mice were significantly decreased, which may partly contribute to decreased GH response to ghrelin in these mice. In Akita mice for comparison, decreased hypothalamic GH-releasing hormone (GHRH) mRNA levels may be responsible for decreased GH response, since maximum GH response to ghrelin needs GHRH. When ghrelin was injected into HFD mice with GHRH coadministrated, GH responses to ghrelin were significantly emphasized. HFD mice injected with low-dose ghrelin and GHRH for 10 days did not show weight gain. These results indicate that low-dose ghrelin and GHRH treatment may restore decreased GH secretion in obesity without worsening obesity.     

Chronic nitric oxide deficiency is associated with altered leutinizing hormone and follicle-stimulating hormone release in ovariectomized rats

Nitric oxide (NO) synthase (NOS) has been found in the gonadotrophs and folliculo-stellate cells of the anterior pituitary. Previous observations from our laboratory suggest that NO may play a role in regulating gonadotropin secretion. Because estrogen secretion by the ovary can influence gonadotropin secretion, we investigated the hypothesis that chronic in vivo NO deficiency has a direct estrogen-independent effect on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Chronic NO deficiency was induced by adding an NOS inhibitor, N-nitro-L-arginine (L-NNA, 0.6 g/l) to the drinking water of ovariectomized (OVX) rats. The control OVX rats were untreated. After 6-8 weeks, the animals were sacrificed, and the pituitaries were removed and perfused continuously for 4 hr in the presence of pulsatile gonadotropin-releasing hormone (GnRH, 500 ng/pulse) every 30 min. S-Nitroso-L-acetyl penicillamine (SNAP, an NO donor, 0.1 mM) or L-nitro-arginine methyl ester (L-NAME, an NOS inhibitor, 0.1 mM) was added to the media and perfusate samples were collected at 10-min intervals. GnRH-stimulated LH and FSH levels were significantly lower in pituitaries from OVX/NO-deficient pituitaries compared with pituitaries from the OVX control group. The addition of SNAP significantly decreased LH and FSH secretion by pituitaries from OVX control animals, but significantly increased their secretion by pituitaries from the OVX/NO-deficient animals. L-NAME also suppressed LH and FSH secretion by pituitaries from the OVX control animals and stimulated their release by pituitaries from the NO-deficient/OVX animals. Immunohistochemistry of frontal sections through the hypothalamus demonstrated that OVX/NO deficiency is associated with increased GnRH in the median eminence. We conclude that NO has a chronic stimulatory effect on LH and FSH release and the subsequent altered secretory responsiveness to NO agonist or antagonist is the result of chronic NO suppression.     

Orexin-A suppresses the pulsatile secretion of luteinizing hormone via beta-endorphin

Orexins, the novel hypothalamic neuropeptides that stimulate feeding behavior, have been shown to suppress the pulsatile secretion of LH in ovariectomized rats. However, the mechanism of this action is still not clear. We examined the effect of naloxone, a specific opioid antagonist, on the suppression of the pulsatile secretion of LH by orexins to determine whether beta-endorphin is involved in this suppressive effect. We administered orexins intracerebroventricularly and injected naloxone intravenously in ovariectomized rats, and we measured the serum LH concentration to analyze the pulsatile secretion. Administration of orexin-A significantly reduced the mean LH concentration and the pulse frequency, but coadministration of naloxone significantly restored the mean LH concentration and the pulse frequency. Administration of orexin-B also significantly reduced the mean LH concentration and the pulse frequency, and coadministration of naloxone did not restore them. These results indicate that orexin-A, but not orexin-B, suppresses GnRH secretion via beta-endorphin.     

Effect of food deprivation on the pulsatile LH release in the cycling and ovariectomized female rat

The effect of food deprivation on the pulsatile release of LH was examined in the normal cycling and the ovariectomized (OVX) adult female rat. In the cycling animals, there were significant decreases in the mean plasma LH levels as well as the frequency and amplitude of the LH pulse 48 h after the onset of food deprivation. On the other hand, food deprivation for up to 72 h did not cause any changes in pulsatile LH release in the OVX animals. No difference in the changes in body weight and blood glucose concentration were found between the cycling and OVX rats throughout the period of food deprivation for up to 96 h. These findings suggest that ovarian factors play an important role in the early manifestation of the effect of food deprivation on pulsatile LH release and that metabolic changes as expressed by decreases in body weight and blood glucose level per se were not the direct causes in the decrease of LH release during the period of food deprivation.     

Characteristics of pulsatile luteinizing hormone secretion in middle-aged ovariectomized rats

Experiments were performed to characterize the pulsatile patterns of circulating luteinizing hormone (LH) in the middle-aged ovariectomized (OVX) rat. Frequent blood samples were taken from OVX rats at 6, 7-8, and 9-10 mo of age, and LH was measured by radioimmunoassay. Rats had been OVX either 2 wk (STO) or 10-20 wk (LTO) previously. Mean LH levels were significantly lower with increasing age, reflecting effects on both pulse amplitude and pulse frequency. Mean LH levels were higher in LTO than STO groups, reflecting primarily an increase in pulse amplitude, but there was also a small, significant decrease in pulse frequency with increased time following OVX. In a second experiment, a random selection of the rats in the STO groups was tested again 10 wk after OVX. A significantly higher number of 9- to 10-mo-old rats had pulsatile patterns at 10 wk than at 2 wk following OVX. Furthermore, mean plasma LH concentrations were higher in all three groups. We conclude that decreases in several parameters of LH secretion are seen in middle-aged OVX rats, at the time when irregularities are first seen in the estrous cycle in the intact rat.     

The role of circulating ghrelin in growth hormone (GH) secretion in freely moving male rats

To examine the physiological significance of plasma ghrelin in generating pulsatile growth hormone (GH) secretion in rats, plasma GH and ghrelin levels were determined in freely moving male rats. Plasma GH was pulsatilely secreted as reported previously. Plasma ghrelin levels were measured by both N-RIA recognizing the active form of ghrelin and C-RIA determining total amount of ghrelin. Mean +/- SE plasma ghrelin levels determined by N-RIA and C-RIA were 21.6 +/- 8.5 and 315.5 +/- 67.5 pM, respectively, during peak periods when plasma GH levels were greater than 100 ng / ml. During trough periods when plasma GH levels were less than 10 ng / ml, they were 16.5 +/- 4.5 and 342.1 +/- 29.8 pM, respectively. There were no significant differences in plasma ghrelin levels between two periods. Next, effect of a GH secretagogue antagonist, [D-Lys-3]-GHRP-6, on plasma GH profiles was examined. There were no significant differences in both peak GH levels and area under the curves of GH (AUCs) between [D-Lys-3]-GHRP-6-treated and control rats. These findings suggest circulating ghrelin in peripheral blood does not play a role in generating pulsatile GH secretion in freely moving male rats.     

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

Ghrelin, a gut-brain peptide, is best known for its role in the stimulation of feeding and growth hormone release. In the brain, orexin, neuropeptide Y (NPY), and ghrelin are parts of a food intake regulatory circuit. Orexin and NPY are also implicated in maintaining wakefulness. Previous experiments in our laboratory revealed that intracerebroventricular injections of ghrelin induce wakefulness in rats. To further elucidate the possible role of ghrelin in the regulation of arousal, we studied the effects of microinjections of ghrelin into hypothalamic sites, which are implicated in the regulation of feeding and sleep, such as the lateral hypothalamus (LH), medial preoptic area (MPA), and paraventricular nucleus (PVN) on sleep in rats. Sleep responses, motor activity, and food intake after central administration of 0.04, 0.2, or 1 mug (12, 60, or 300 pmol) ghrelin were recorded. Microinjections of ghrelin into the LH had strong wakefulness-promoting effects lasting for 2 h. Wakefulness was also stimulated by ghrelin injection into the MPA and PVN; the effects were confined to the first hour after the injection. Ghrelin's non-rapid-eye-movement sleep-suppressive effect was accompanied by attenuation in the electroencephalographic (EEG) slow-wave activity and changes in the EEG power spectrum. Food consumption was significantly stimulated after microinjections of ghrelin into each hypothalamic site. Together, these results are consistent with the hypothesis that forebrain ghrelinergic mechanisms play a role in the regulation of vigilance, possibly through activating the components of the food intake- and arousal-promoting network formed by orexin and NPY.     

顺铂化疗对下丘脑、血浆ghrelin和orexin 表达的影响

目的:观察顺铂化疗对下丘脑、血浆ghrelin、orexin表达和摄食量的影响。方法:Real-time PCR、ELISA法观察顺铂对大鼠下丘脑、血浆ghrelin、orexin表达及摄食量的影响;19名接受顺铂经导管动脉灌注化疗(TAI)的肝细胞患者(HCC),ELISA法检测化疗前和化疗后血浆ghrelin、orexin的变化,用直观类比标度(VAS)(0-10)评估食欲和摄食量。结果:每日腹腔注射顺铂6 mg/kg,1-5 d大鼠摄食量均显著减少(P0.05),且1-4 d血浆酰化ghrelin显著降低(P0.05),5d时浓度仍低于对照组,但无统计学意义。血浆非酰化ghrelin和总的血浆ghrelin没有明显变化(P0.05),而1-5天血浆orexin水平均明显降低(P0.05);顺铂注射1 d后,大鼠下丘脑ghreilin和orexin的mRNA表达量均显著减少(P0.05),ghrelin mRNA变化持续3 d,orexin mRNA在化疗后5 d仍低于对照组(P0.05);肝细胞癌患者化疗后1至8 d的摄食量明显降低,1 d和2 d时的血浆酰化ghrelin显著低于化疗前水平(P0.05)。3 d时逐渐恢复,化疗后3 d、4 d和7 d时血浆酰化ghrelin浓度与化疗前无统计学差异(P0.05)。血浆非酰化ghrelin和总的血浆ghrelin没有明显变化(P0.05);化疗后1~4 d时血浆orexin浓度均显著降低(P0.05),化疗后7 d时orexin基本恢复到化疗前水平(P0.05)。结论:顺铂可降低大鼠下丘脑和血浆ghrelin、orexin的mRNA表达,HCC的TAI会降低血浆酰化ghrelin、orexin、和摄食量。     

Effect of chronic hyperghrelinemia on ingestive action of ghrelin

The stomach hormone ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Systemic administration of ghrelin will cause elevations in growth hormone (GH) secretion, food intake, adiposity, and body growth. Ghrelin also affects insulin secretion, gastric acid secretion, and gastric motility. Several reports indicate that repeated or continuous activation of GHS-R by exogenous GHSs or ghrelin results in a diminished GH secretory response. The purpose of this study was to examine the extent to which the acute stimulation of food intake by exogenous ghrelin is altered by chronic hyperghrelinemia in transgenic mice that overexpress the human ghrelin gene. The present findings show that the orexigenic action of exogenous ghrelin is not diminished by a chronic hyperghrelinemia and indicate that the food ingestive pathway of the GHS-R is not susceptible to desensitization. In contrast, the epididymal fat pad growth response, like the GH response, to exogenous ghrelin is blunted in ghrelin transgenic mice with chronic hyperghrelinemia.     

Effects of neuromedin U on the pulsatile LH secretion in ovariectomized rats in association with feeding conditions

We examined the effects of intracerebroventricular injection of neuromedin U (NMU), at a dose that is reported to induce satiety in rats, on the pulsatile luteinizing hormone (LH) secretion in adult ovariectomized (OVX) rats under a normal feeding or a 48-h fasted condition. In OVX rats under the normal feeding condition, injection of NMU (1 nmol/3 microl) significantly decreased the mean LH concentration without affecting the frequency or amplitude of LH pulses, but under the 48-h fasted condition, it significantly decreased the mean LH concentration and the frequency of LH pulses without affecting the amplitude. The interpulse interval was significantly lengthened by NMU injection under the normal and the 48-h fasted condition, but the effect under the 48-h fasted condition was greater than under the normal feeding condition. We also confirmed that the 48-h fasted condition per se did not affect the pulsatile LH secretion in OVX rats. We suggest that NMU and fasting synergistically inhibit the pulsatile LH secretion, even though NMU has been said to act as a satiety factor.     

Orexins, orexigenic hypothalamic neuropeptides, suppress the pulsatile secretion of luteinizing hormone in ovariectomized female rats.

It is well known that feeding disorders are deeply related to reproductive dysfunction, and some feeding regulatory factors may modulate the reproductive function. We examined the effect of orexins, the newly discovered orexigenic hypothalamic neuropeptides, on the pulsatile secretion of LH to clarify their influence on the reproductive function. We administered orexins or saline into the third ventricle of bilaterally ovariectomized (OVX) rats, and measured the serum LH concentration by RIA in blood samples drawn every 6 min for 2 hours to analyze the pulsatile secretion. In the orexin-treated groups, the mean LH concentration and the pulse frequency were significantly reduced (p < 0.01), but the pulse amplitude did not differ significantly. These data indicate that orexins suppress the pulsatile secretion of LH by influencing GnRH neurons at the hypothalamic level.     

Different neuroendocrine systems modulate pulsatile luteinizing hormone secretion in photosuppressed and photorefractory ewes.

The objective of this study was to determine whether two photoperiod regimens that induce anestrus in the ewe-short-day photorefractoriness (SDPR) and long-day photosuppression (LDPS)--act by different neuronal mechanisms. In separate experiments, ovary-intact (INTACT), ovariectomized (OVX), and ovariectomized estradiol-treated (OVX + E) ewes were subjected to three different photoperiodic regimens that resulted in reproductive quiescence: (1) exposure to long days (16L:8D), which caused photosuppression (INTACT, n = 9; OVX, n = 6; OVX + E, n = 5; (2) prolonged exposure to short days (10L:14D)), which caused photorefractoriness (INTACT, n = 10; OVX, n = 6; OVX + E, n = 5); (3) exposure to natural photoperiod, which induced seasonal anestrus (INTACT, n = 11; OVX, n = 6; OVX + E, n = 5). Effect of photoregimen was monitored by measuring progesterone or LH. Drug challenges were made after two sequential estrous cycles were missed in INTACT ewes, after mean LH concentrations dropped below 1 ng/ml in OVX + E ewes, and after LH interpulse intervals increased in OVX ewes. Effects of drug on LH pulse pattern were determined by taking blood samples at 12-min intervals for 8 h after i.v. diluent injection; then for 8 h after i.v. injection of cyproheptadine, a serotonin antagonist (3 mg/kg); and again 7 days later after i.v. injection of diluent or pimozide, a dopamine antagonist (0.25 mg/kg). Cyproheptadine had little effect except to decrease (p = 0.05) mean LH in INTACT anestrous ewes and decrease (p less than 0.01) pulse amplitude in OVX + E SDPR ewes. Pimozide did not affect LH pulse frequency in LDPS ewes. However, pimozide increased LH pulse frequency (p less than 0.005) and mean concentrations (p less than 0.005) in SDPR OVX + E ewes, whereas it suppressed LH pulse frequency (p less than 0.05) and amplitude (p less than 0.03) in SDPR INTACT and SDPR OVX ewes. The results suggest that (1) the role of the dopaminergic system differs in SDPR and LDPS ewes, and that different neuronal systems may effect SDPR and LDPS, (2) the effect of pimozide in SDPR ewes is altered by ovarian steroids, and (3) the serotonergic system has relatively little role in regulating pulsatile LH secretion in any of the three different states of anestrus.     

Effects of food restriction and restoration on gonadotropin and growth hormone secretion in immature male rats

This experiment concerned the changing patterns in secretion of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and growth hormone (GH) under conditions of food restriction and subsequent catch-up growth. Weanling male rats were given either restricted (4 g food/day) or unrestricted access to food until 60 days of age. At this age, food-restricted rats weighed only 25% as much as rats fed ad libitum. Food restriction resulted in a dramatic decrease in the frequency of LH and GH pulses, and in the amplitude of GH pulses. It also slightly but significantly decreased mean blood levels of FSH (which was not secreted in a pulsatile manner in 60-day-old controls fed ad libitum). When restricted rats were given unrestricted access to food, frequency of LH and GH pulses and mean levels of FSH increased significantly and simultaneously within 2 days in half of the animals. Only an additional 8-10% of their body weight decrement was recovered at this time. After 10 days of food restoration, when restricted rats still weighed 50% less than controls, their secretory patterns of all three hormones were not significantly different from those of controls. Thus, recovery of gonadotropin and GH secretion was relatively rapid. Except for the quantitatively lesser impact of food restriction on FSH secretion, there was no evidence of any priorities in the secretion of the three hormones. Under conditions of rapid catch-up growth, the secretory patterns of LH, FSH, and GH appeared to develop simultaneously.     

Altered negative feedback response to ovariectomy and estrogen in prepubertal restricted-diet rats

Studies were conducted to explore the hypothesis that the delayed sexual maturation of female rats induced by reduced food intake (R) may result partially from an altered negative feedback response to estrogen. Animals were placed on 60% of normal food intake at 20 days of age. Controls (C) were fed ad libitum. Rats were used for three different experiments at 31-32 days of age. In Experiment I, rats were ovariectomized (OVX) and injected subcutaneously for 4 days with varying doses of estradiol benzoate (EB). They were killed the day after the last injection. In Experiment II, rats were ovariectomized and killed in groups at 4, 12, 24, 48, 72, and 120 h after OVX. In Experiment III, they were castrated and 1 wk later received a single injection of 0.5 microgram EB. Groups were killed at 1, 2, 4, 8, and 24 h after injection. Sera from all experiments were assayed for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin. Results of Experiment I indicate that the efficacy of EB for suppressing LH, but not FSH, secretion is increased significantly in R rats. In Experiment II, OVX resulted in a delayed increase in serum LH, but not FSH, concentrations of R rats when compared to C animals. Results of Experiment III indicate a delayed, but more prolonged, suppression of LH secretion by EB in R rats when compared to C rats. Prolactin secretion, on the other hand, increased earlier in R rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Obestatin acts in brain to inhibit thirst

Derived from the same prohormone, obestatin has been reported to exert effects on food intake that oppose those of ghrelin. The obestatin receptor GPR39 is present in brain and pituitary gland. Since the gene encoding those two peptides is expressed also in those tissues, we examined further the possible actions of obestatin in vivo and in vitro. Intracerebroventricular administration of obestatin inhibited water drinking in ad libitum-fed and -watered rats, and in food-and water-deprived animals. The effects on water drinking preceded and were more pronounced than any effect on food intake, and did not appear to be the result of altered locomotor/behavioral activity. In addition, obestatin inhibited ANG II-induced water drinking in animals provided free access to water and food. Current-clamp recordings from cultured, subfornical organ neurons revealed significant effects of the peptide on membrane potential, suggesting this as a potential site of action. In pituitary cell cultures, log molar concentrations of obestatin ranging from 1.0 pM to 100 nM failed to alter basal growth hormone (GH) secretion. In addition, 100 nM obestatin failed to interfere with the stimulation of GH secretion by GH-releasing hormone or ghrelin and did not alter the inhibition by somatostatin in vitro. We conclude that obestatin does not act in pituitary gland to regulate GH secretion but may act in brain to alter thirst mechanisms. Importantly, in rats the effects of obestatin on food intake may be secondary to an action of the peptide to inhibit water drinking.     

Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion

Ghrelin is a recently discovered stomach hormone that stimulates pituitary growth hormone (GH) secretion potently. The purpose of these experiments was to test the hypothesis that a stomach-ghrelin-pituitary-GH axis exists in which either an elevation or reduction in systemic GH levels will exert a negative or positive feedback action, respectively, on stomach ghrelin homeostasis. In rats, GH administration decreased stomach ghrelin mRNA levels and plasma ghrelin levels significantly. In GH-releasing hormone (GHRH) transgenic mice, GHRH overexpression decreased stomach ghrelin peptide levels when compared with control mice. In aged rats (25 months) stomach ghrelin mRNA and peptide levels and plasma ghrelin levels were decreased when compared with young rats (5 months). Because GH secretion is reduced in aged rats, the elevated stomach ghrelin production and secretion may reflect a decreased GH feedback on stomach ghrelin, homeostasis, and secretion. Together, these findings suggest that endogenous pituitary GH exerts a feedback action on stomach ghrelin homeostasis and support the hypothesis that a stomach-ghrelin-pituitary GH axis exists.     

Hypophysectomy Prevents Ghrelin-Induced Adiposity and Increases Gastric Ghrelin Secretion in Rats

Objective: The novel gastric hormone ghrelin has recently been identified as an important modulator of energy homeostasis. Leptin-responsive hypothalamic neuropeptide Y/Agouti-related protein neurons are believed to mediate afferent ghrelin signals. Little is known, however, about ghrelin-induced efferent signals. We therefore investigated if hypothalamic-pituitary axes have a role in transferring ghrelin-induced changes of energy balance to the periphery. Research Methods and Procedures: We subcutaneously injected hypophysectomized, as well as adrenalectomized, thyroidectomized, and sham-operated control rats with GH secretagogues [ghrelin, growth hormone (GH)-releasing peptide] for 1 week. Body weight, food intake, and body composition (chemical carcass analysis) were analyzed and compared with vehicle-treated controls. In addition, we quantified circulating levels of endogenous ghrelin in hypophysectomized and GH–treated normal rats. Results: GH-secretagogue treatment of sham-operated control rats dose-proportionally increased food intake, body weight, and fat mass compared with vehicle-injected controls (p < 0.01). These effects, however, were not observed in ghrelin-treated hypophysectomized, thyroidectomized, or adrenalectomized rats, indicating an essential role for the pituitary axis in ghrelin-induced adiposity. Circulating levels of endogenous ghrelin were reduced by administration of GH in normal rats and were about 3-fold higher in hypophysectomized rats (n = 20, p = 0.001), suggesting a regulatory feedback loop involving the stomach and the pituitary to regulate gastric ghrelin secretion. Discussion: According to these results, the endocrine pituitary is mediating ghrelin-induced changes toward a positive energy balance and is involved in the regulation of ghrelin secretion through a gastro-hypophyseal feedback loop.     

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

Growth hormone (GH) secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (<1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.     

Inhibitory effects of cysteamine on neuroendocrine function

The action of cysteamine on anterior pituitary hormone secretion was studied in vivo using conscious, freely moving male rats and in vitro using anterior pituitary cells in monolayer culture. Administration of 500 micrograms cysteamine into the lateral cerebral ventricles of normal rats caused the complete inhibition of pulsatile GH secretion for a minimum of 6 h. This treatment also significantly decreased plasma concentrations of LH for at least 6 h in orchiectomized rat, TSH in short-term (0.5 month) thyroidectomized rats, and PRL in long-term (6 months) thyroidectomized rats. The in vivo stimulation of GH, LH, TSH and PRL with their respective releasing hormones 60 min after administration of cysteamine was not different from the response observed in rats pretreated with saline except for PRL where cysteamine pretreatment significantly inhibited the expected PRL increase. In vitro, 1 mM cysteamine decreased basal and TRH stimulated PRL release while not affecting basal or stimulated GH, LH, TSH and ACTH secretion. These data demonstrate the dramatic and wide-ranging effects of cysteamine on anterior pituitary hormone secretion. This action appears to be mediated through hypothalamic pathways for GH, LH and TSH and through a pituitary pathway for PRL.     

Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents

Leptin, an adipocytokine that suppresses appetite and may regulate neuroendocrine pathways, is low in undernourished states like anorexia nervosa (AN). Although leptin exhibits pulsatility, secretory characteristics have not been well described in adolescents and in AN, and the contribution of hypoleptinemia to increased growth hormone (GH) and cortisol in AN has not been explored. We hypothesized that hypoleptinemia in AN reflects decreased basal and pulsatile secretion and may predict increased GH and cortisol levels. Sampling for leptin, GH, cortisol, and ghrelin was performed every 30 min (from 2000 to 0800) in 23 AN and 21 controls 12-18 yr old, and data were analyzed using Cluster and deconvolution methods. Estradiol, thyroid hormones, and body composition were measured. AN girls had lower pulsatile and total leptin secretion than controls (P < 0.0001) subsequent to decreased burst mass (P < 0.0001) and basal secretion (P = 0.02). Nutritional markers predicted leptin characteristics. In a regression model including BMI, body fat, and ghrelin, leptin independently predicted GH burst interval and frequency. Valley leptin contributed to 56% of the variability in GH burst interval, and basal leptin and fasting ghrelin contributed to 42% of variability in burst frequency. Pulsatile leptin independently predicted urine free cortisol/creatinine (15% of variability). Valley leptin predicted cortisol half-life (22% of variability). Leptin predicted estradiol and thyroid hormone levels. In conclusion, hypoleptinemia in AN is subsequent to decreased basal and pulsatile secretion and nutritionally regulated. Leptin predicts GH and cortisol parameters and with ghrelin predicts GH burst frequency. Low leptin and high ghrelin may be dual stimuli for high GH concentrations in undernutrition.