Fernando Cordido

Serum leptin levels in women throughout pregnancy and the postpartum period and in women suffering spontaneous abortion

In pregnancy, important changes occur in the body weight of the mother, caused by sodium and water retention and by an increase in body fat tissue, but the mechanisms that regulate maternal and foetal changes in fat mass are poorly understood. Leptin is a hormone produced by adipocytes in order to regulate food intake and energy expenditure at the hypothalamic level in man. In order to verify whether leptin participates in the changes in body composition during pregnancy and postpartum, 630 healthy women were studied at specific time periods and leptin and auxological parameters were determined.

Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy

Context It has been reported that metformin might modify thyroid hormone economy. In two retrospective studies, initiation of treatment with metformin caused suppression of TSH to subnormal levels. Objective To prospectively evaluate if administration of metformin to obese, diabetic patients with primary hypothyroidism on stable thyroxine replacement doses modifies TSH levels. Patients and methods Eight obese, diabetic postmenopausal women with primary hypothyroidism participated in the study. They received 1,700xa0mg of metformin daily for 3xa0months. Weight, TSH, free T4, and free T3 levels were measured at baseline, 3xa0months after metformin initiation and 3xa0months after its withdrawal. Results After 3xa0months of on metformin, mean TSH was significantly lower than basal TSH (3.11xa0±xa00.50xa0μUI/ml vs. 1.18xa0±xa00.36xa0μUI/ml; Pxa0=xa00.01). Mean TSH 3xa0months after metformin withdrawal was 2.21xa0±xa00.37xa0μUI/ml, significantly higher than TSH after metformin (Pxa0=xa00.05), but not different from basal TSH. Mean fT4 level increased during metformin administration (basal fT4: 1.23xa0±xa00.06xa0ng/dl, fT4 after metformin: 1.32xa0±xa00.04xa0ng/dl; Pxa0=xa0ns), and decreased after its withdrawal (fT4 3xa0months after metformin withdrawal: 1.15xa0±xa00.05xa0ng/dl; vs. 3xa0months after metformin, Pxa0=xa00.04; vs. basal; Pxa0=xa0ns). Conclusions In obese, diabetic patients with primary hypothyroidism on thyroxine replacement treatment, short-term metformin administration is associated with a significant fall in TSH.

Marked GH secretion after ghrelin alone or combined with GH-releasing hormone (GHRH) in obese patients.

objectivesu2002 Ghrelin is a 28‐amino‐acid peptide, predominantly produced by the stomach. It displays a strong GH‐releasing activity mediated by the hypothalamus–pituitary GH secretagogue (GHS)‐receptor (GHS‐R). There are different studies that suggest the importance of ghrelin in feeding and weight homeostasis. In obesity there is a markedly decreased GH secretion. For both children and adults, the greater the body mass index (BMI), the lower the GH response to provocative stimuli, including the response to GHRH. However, the response to the natural GH secretaogogue ghrelin is unclear at the present time. The aim of the present study was to evaluate the GH response to ghrelin alone or combined with GHRH in a group of obese patients, in order to further understand the deranged GH secretory mechanisms in obesity and to clarify the mechanism of action of ghrelin.

Ghrelin and lipid metabolism: key partners in energy balance

Ghrelin, the endogenous ligand of the GH secretagogue receptor, has a pleiotropic role in the modulation of energy balance. Recent evidence has demonstrated that besides its orexigenic role, ghrelin regulates central and peripheral lipid metabolism through specific control of hypothalamic AMP-activated protein kinase (AMPK), a critical metabolic gauge regulating both cellular and whole-body energy homeostasis. In this review, we summarize the new milestones of ghrelins actions on energy balance, with particular focus on its molecular interaction with hypothalamic AMPK and fatty acid metabolism. Understanding this new metabolic pathway can provide new therapeutic targets for the treatment of obesity and the metabolic syndrome.

Study of insulin-like growth factor I in human obesity.

In obesity there is a decrease in basal and stimulated GH secretion. IGF-I, which has negative feedback effects on GH secretion, could be the initial mediator of such alterations. We studied IGF-I levels in obese subjects and their relationship to the obesity level and GH secretion. We determined plasma IGF-I, basal and stimulated GH in 30 normal and 30 obese women and related these variables to obesity indices (body mass index, BMI, and % overweight). Baseline plasma GH values were 1.2 +/- 0.3 and 2.3 +/- 0.6 micrograms/l in obese subjects and controls, respectively (NS). Mean peak GH secretion after stimuli were 11.2 +/- 1.4 and 34.4 +/- 5.6 micrograms/l in obese subjects and controls, respectively (p less than 0.001). Plasma IGF-I were 1.0 +/- 0.1 U/ml and 0.7 +/- 0.1 U/l in obese subjects and controls, respectively (NS). There was a significant negative correlation between plasma IGF-I and age (r = -0.55, p less than 0.001) and a significant negative correlation between mean peak GH secretion and weight (r = -0.60, p less than 0.001), BMI (r = -0.64, p less than 0.001) and percentage of ideal body weight (r = -0.67, p less than 0.001). We did not find any correlation between IGF-I and indices of overweight. These data suggest that the reduced GH secretion found in obesity is not related to a negative feedback inhibition by elevated levels of IGF-I and that adiposity is not associated with a decline in IGF-I levels. We confirm the existence of a negative correlation between GH secretion and obesity indices.

EFFECT OF ENHANCEMENT OF ENDOGENOUS CHOLINERGIC TONE WITH PYRIDOSTIGMINE ON GROWTH HORMONE (GH) RESPONSES TO GH‐RELEASING HORMONE IN PATIENTS WITH CUSHING'S SYNDROME

Growth hormone (GH) secretion in patients with Cushings syndrome is diminished to all the stimuli tested so far but the precise mechanisms through which this occurs are unknown. In order to investigate whether increased somatostatinergic tone might be responsible for this alteration, we studied the effect of pyridostigmine (120 mg p. o. at ‐60 min), which activates cholinergic synapses and thus suppresses hypothalamic somatostatin release on GH responses to GHRH (100 μg, i. v. at 0 min), in six patients with Cushings syndrome. We found that while pyridostigmine markedly potentiated GH responses to GHRH, in all the normal subjects tested (n=12), neither GHRH alone nor GHRH plus pyridostigmine elicited any increase in GH secretion in any of the patients with Cushings syndrome. This suggests that chronic glucocorticoid excess induces marked alterations in the hypothalamic control of GH secretion.

The decreased growth hormone response to growth hormone releasing hormone in obesity is associated to cardiometabolic risk factors.

The aim of the present study was to evaluate the relationship between GHRH-induced GH secretion in obese premenopausal women and cardiovascular risk markers or insulin resistance. Premenopausal obese women, aged 35–52 years, were studied. GH secretion, IGF-I, serum cardiovascular risk markers, insulin, leptin, mid-waist and hip circumference, total body fat, and truncal fat were measured. Subjects were classified as meeting the criteria for GH deficiency (GHD) when peak GH after stimulation with GHRH was ≤3u2009μg/L. Mean total and LDL cholesterol, fasting insulin, and HOMA-IR were all higher, in subjects who would have been classified as GH-deficient compared with GH-sufficient. Peak GH secretion after stimulation was inversely associated with fasting insulin (R = −0.650, P = .012), HOMA-IR (R = −0.846, P = .001), total cholesterol (R = −0.532, P = .034), and LDL cholesterol (R = −0.692, P = .006) and positively associated with HDL cholesterol (R = 0.561, P = .037). These data strongly suggest a role for insulin resistance in the decreased GH secretion of obesity and that the blunted GH secretion of central obesity could be the pituitary expression of the metabolic syndrome.

Ghrelin and Growth Hormone Secretagogues, Physiological and Pharmacological Aspect

The first growth hormone secretagogues (GHSs) were discovered by Bowers et al. in 1977. In 1996 the GHSs receptor (GHS-R 1a) was cloned. The endogenous ligand for this receptor, ghrelin, was not identified until 1999. Synthetic molecules termed GHSs are substances that stimulate growth hormone (GH) release, via a separate pathway distinct from GH releasing hormone (GHRH)/somatostatin. Ghrelin displays strong GH-releasing activity through the activation of the GHS-R 1a. Apart from stimulating GH secretion, ghrelin and many synthetic GHSs: 1) stimulate prolactin and ACTH secretion; 2) negatively influence the pituitary-gonadal axis; 3) stimulate appetite and positive energy balance; 4) modulate pancreatic endocrine function and affect glucose levels; 5) have cardiovascular actions. The control of ghrelin secretion is not well established at present, although nutrition is an important regulator. Investigators have exploited the ability of GHSs and ghrelin to release GH by mechanisms different from GHRH as a diagnostic tool, which is the present main clinical use of some GHSs. As an alternative to GH, GH deficient conditions could be treated with any substance which would release endogenous GH, such as synthetic GHSs. It is likely that GHSs, acting as either agonists or antagonists on different pathophysiological processes, might have some other clinical impact and therapeutic potential. At least theoretically ghrelin receptor antagonists could be anti-obesity drugs, as blockers of the orexigenic signal from the gastrointestinal tract to the brain. Inverse agonists of the ghrelin receptor, by blocking the constitutive receptor activity, might lower the set-point for hunger between meals.

Food intake regulating-neuropeptides are expressed and regulated through pregnancy and following food restriction in rat placenta

BackgroundNeuropeptide Y (NPY), agouti related peptide (AgRP), cocaine and amphetamine-regulated transcript (CART) and melanocortins, the products of the proopiomelanocortin (POMC), are hypothalamic peptides involved in feeding regulation and energy homeostasis. Recent evidence has demonstrated their expression in rat and human placenta.MethodsIn the current study, we have investigated the expression of those neuropeptides in the rat placenta by real-time PCR using a model of maternal food restriction.ResultsOur results showed that placental-derived neuropeptides were regulated through pregnancy and following food restriction.ConclusionThese data could indicate that placental-derived neuropeptides represent a local regulatory circuit that may fine-tune control of energy balance during pregnancy.

Ghrelin in Obesity, Physiological and Pharmacological Considerations

The aim of this review is to summarize the physiological and pharmacological aspects of ghrelin. Obesity can be defined as an excess of body fat and is associated with significant disturbances in metabolic and endocrine function. Obesity has become a worldwide epidemic. In obesity there is a decreased growth hormone (GH) secretion, and the altered somatotroph secretion in obesity is functional. Ghrelin is a peptide that has a unique structure with 28 amino-acids and an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. The pathophysiological mechanism responsible for GH hyposecretion in obesity is probably multifactorial, and there is probably a defect in ghrelin secretion. Ghrelin is the only known circulating orexigenic factor, and has been found to be reduced in obese humans. Ghrelin levels in blood decrease during periods of feeding. Due to its orexigenic and metabolic effects, ghrelin has a potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal and cardiac disease, and age-related frailty. Theoretically ghrelin receptor antagonists could be employed as anti-obesity drugs, blocking the orexigenic signal. By blocking the constitutive receptor activity, inverse agonists of the ghrelin receptor may lower the set-point for hunger, and could be used for the treatment of obesity. In summary, ghrelin secretion is reduced in obesity, and could be partly responsible for GH hyposecretion in obesity, ghrelin antagonist or partial inverse agonists should be considered for the treatment of obesity.