Biomedical subjects

Carlos Dieguez

Publications and source records attributed to Carlos Dieguez.

43 records · Page 3Linked to original sources

PubMed2002

The role of leptin in reproduction: experimental and clinical aspects.

The discovery of the adipocyte-produced hormone leptin has greatly changed the field of obesity research and future treatment as well as our understanding of energy homeostasis in man. In addition to its relevant role as a metabolic adaptor to overweight and fasting states, new and previously unsuspected neuroendocrinological roles have emerged for leptin. In reproduction, leptin is implicated in fertility regulation and appears as a permissive factor for puberty. In particular, various sets of data suggest that leptin may serve as a signal to the central nervous system (CNS) with information on the critical amount of adipose tissue stores that is necessary for gonadotropin-releasing hormone (GnRH) secretion and pubertal activation of the hypothalamic-pituitary-gonadal axis. Leptin also acts at the periphery, directly on the ovary and testis where it may control steroidogenesis, although the exact role of intragonadal action in the physiology and pathophysiology of the human reproductive system needs to be further elucidated. Furthermore, relevant gender-based differences in leptin levels exist, with higher levels in women, even at birth, and which persist throughout life. In adult life, there is experimental evidence that leptin is a permissive factor for the menstrual cycle, with a regulatory role exerted at hypothalamic, pituitary and gonadal levels, and with severe changes in pregnancy and postpartum. Moreover, leptin is present in both human and commercial milk, and may play a role in the adaptive responses of the newborn.

Adult↗

PubMed2002

Ghrelin is no longer able to stimulate growth hormone secretion in patients with Cushing's syndrome but instead induces exaggerated corticotropin and cortisol responses.

Growth and growth hormone (GH) secretion are blunted or severely impeded in chronic hypercortisolism and in patients with Cushing's syndrome. A mechanistic explanation for the effect however has yet to be provided. On the other hand, several properties of ghrelin, a new peptide recently identified as the endogenous ligand of the GH secretagogue receptor, are still largely unknown. The two aims of this study were to observe whether ghrelin-mediated GH secretion was altered, and to characterize the corticotropin (ACTH) and cortisol response to this new stimulus in patients with Cushing's disease. Ten patients with active Cushing's disease (6 harboring microadenomas and 4 with macroadenomas) and 10 sex- and age-matched controls were studied. Ghrelin was administered at a dose of 1 microg/kg i.v. and GH, ACTH and cortisol analyzed in duplicate. In control women, ghrelin induced GH secretion to levels of 74.4 +/- 12.8 microg/l, while chronic hypercortisolism severely reduced the ghrelin-mediated GH release in all patients with Cushing's disease (peak values 17.7 +/- 5.2 microg/l). The slightly, but significantly higher adiposity of patients vs. controls may have contributed to the effect, since a significant negative correlation (r = 0.639) was found between the amplitude of the GH peak and body mass index. In control women, ghrelin increased ACTH and cortisol levels, with peaks at 57.4 +/- 19.0 ng/l and 162 +/- 16 microg/l, respectively. This secretion was enhanced in Cushing's syndrome patients, with ACTH and cortisol values of 380.7 +/- 109.8 ng/l and 338 +/- 81 microg/l respectively, both significantly higher than in controls. In conclusion, ghrelin-induced GH secretion was severely blunted in patients with active Cushing's syndrome, in addition to a remarkable hyper-response in ACTH and cortisol secretion. These findings could have implications for the understanding of the physiology and physiopathology of interactions between GH and ACTH regulation.

Adrenocorticotropic Hormone↗

PubMed2002

The impact of cranial irradiation on GH responsiveness to GHRH plus GH-releasing peptide-6.

Patients treated with cranial radiation are at risk of GH deficiency (GHD). We evaluated somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool in relation to the impact of radiation damage to the hypothalamic-pituitary unit. The GH-releasing effect of GHRH plus GH secretagogue [GH-releasing peptide (GHRP)-6] (GHRH+GHRP-6) was studied in 22 adult patients (age, 23.2 +/- 1.4 yr; 8 female and 14 male; mean body mass index, 22.6 +/- 0.7 kg/m(2)) who received cranial radiation for primary brain tumor distant from hypothalamic-pituitary region 7.6 +/- 0.7 yr before GH testing. Two stimulatory tests for GH secretion were employed: insulin tolerance test (ITT, 0.15 IU/kg regular insulin i.v. bolus); and GHRH+GHRP-6 test: GHRH (Geref Serono, Madrid, Spain; l microg/kg) plus GHRP-6 (CLINALFA, Laufelingen, Switzerland; 1 microg/kg) as i.v. bolus. Serum GH was measured (Delphia; Perkin Elmer, Wallac, Turku, Finland) at -30, -15, 0, 15, 30, 45, 60, 90, and 120 min. Anterior pituitary function was normal in all except in 1 female with hyperprolactinemia. Twelve out of 22 irradiated patients were GH-deficient (GHD) with both tests. Eleven out of 22 (50%) irradiated patients were severely GHD, according to the ITT (GH < 3 microg/liter; mean GH peak, 1.5 +/- 0.5 microg/liter). In 9 irradiated patients, in whom ITT was performed as well, mean peak GH after the GHRH+GHRP-6 test was 6.2 +/- 0.8 microg/liter, which is considered as severe GHD, according to our own cut-off for the test (peak GH < 10 microg/liter). GH responses to both tests were highly concordant, but the differential in the GH peak concentrations between GHD and non-GHD irradiated patients was significantly larger for the GHRH+GHRP-6 test than that for the ITT. The 2 discordant responses, i.e. poor response to the ITT and good response to the GHRH+GHRP-6 test, were found in 1 hyperprolactinemic female patient and in 1 other female. One irradiated patient was diagnosed as GHD only with the combined test, because ITT was contraindicated because of epilepsy. PRL and cortisol responses to ITT were normal in all irradiated patients and did not depend on the GH status. IGF-I levels were not informative or discriminative between the GHD and non-GHD irradiated adult patients. In conclusion, the use of GH secretagogues plus GHRH is an easy, reliable and accurate way of assessing GH secretion in cranially irradiated patients. Impairment of the GH releasable pool in the irradiated patients, with a maximal provocative test, reflects alterations in the hypothalamic-pituitary unit caused by radiotherapy.

Adolescent↗

PubMed2002

Evidence of free leptin in human seminal plasma.

Leptin is an adipose tissue-secreted hormone that actively participates in the regulation of energy homeostasis. Besides this principal role, leptin has been implicated in a large variety of neuroendocrine, paracrine, and autocrine actions involved in the regulation of reproductive function in both experimental animals and humans. Although the participation of leptin in female reproduction is well established, any role in male reproductive function is at best tenuous. The aim of this study was to ascertain whether true leptin is present in human seminal fluid and the tissue of its production. Pooled human seminal plasma obtained from healthy donors showed by direct radioimmunoassay (RIA) the presence of radioimmunoassayable leptin. Serial dilutions of unextracted semen paralleled the RIA standard curve, also devoid of interference in the assay. To prove that this activity was true leptin, seminal plasma was subjected to size-exclusion chromatography, which showed that leptin immunoreactivity eluted with the same partition coefficient as cold leptin, 125I-leptin, and 125I-leptin preincubated with seminal plasma. The results demonstrate that true leptin was present in semen in a free form, i.e., without binding proteins. The presence of leptin charge variants in seminal plasma was assessed by anion-exchange chromatography, which showed two peaks of leptin inmunoreactivity, while 125I-leptin eluted as a single peak. Preincubation of 125I-leptin with seminal fluid converted the single peak into a double peak, indicating that components of the seminal fluid introduce a charge variation in leptin. Leptin levels in seminal plasma of 40 healthy men were 0.95+/-0.19 ng/mL while in 5 vasectomized men the levels were 0.92+/-0.25 ng/mL, suggesting that testicular tissues were not the source of seminal leptin. No correlation was observed between leptin concentrations in semen and the physical characteristics of semen samples or physical characteristics of spermatozoids, such as concentration, motility, vitality, or morphology. In conclusion it was unambiguously demonstrated that human leptin is present in seminal fluid, with at least two charge variants and no binding proteins, the most likely source being either seminal vesicles or prostate tissue. The role of seminal fluid leptin in the male reproductive function or sperm capacitation is at present unknown.

Adult↗

PubMed2002

Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine.

OBJECTIVE: It has recently been shown that increased body weight is associated with prolactinomas and that weight loss occurs with normalization of prolactin levels. On the other hand, decreased dopaminergic tone in humans is well correlated with obesity. The objective of this study was to correlate changes in prolactin levels with leptin and body mass index (BMI) in patients with prolactinomas treated with the long-acting dopamine agonist bromocriptine (BC). METHODS: Eleven female and twelve male patients, aged 36.7+/-2.6 years with BMI in males of 30.4+/-1.7 kg/m(2) and in females of 24.4+/-1.2 kg/m(2), were evaluated after 1 and 6 months and 11 patients were further evaluated after 2 years of BC therapy. Plasma prolactin is presented as the mean of four samples taken daily. Serum leptin was determined in the pooled serum from three samples taken at 15-min intervals at 0800 h after an overnight fast. Multivariate linear regression and repeated measures analysis of covariance were used. RESULTS: In males, pretreatment prolactin levels were 71 362+/-29 912 mU/l while leptin levels were 14.9+/-1.8 microg/l. In females, pretreatment prolactin levels were 11 395+/-5839 mU/l and leptin levels were 16.7+/-2.5 microg/l. The sexual dimorphism of serum leptin levels at initial presentation was preserved after adjusting for BMI and prolactin-induced hypogonadism. After 1 month of therapy, prolactin levels significantly decreased (males: 17 618+/-8736 mU/l, females: 3686+/-2231; P<0.05), BMI did not change (males: 30.2+/-1.7 kg/m(2), females: 24.1+/-1.2 kg/m(2); P>0.05), while serum leptin levels decreased (males: 12.5+/-1.5 microg/l, females: 13.6+/-2.1 microg/l; P<0.05). After 6 months of treatment, prolactin further decreased (males: 3456+/-2101 mU/l, females: 677+/-360 mU/l; P<0.05) as did BMI (males: 28.6+/-1.6 kg/m(2), females 23.1+/-1.0 kg/m(2); P<0.05). The difference was more pronounced in male patients. Leptin levels were 12.8+/-2.8 microg/l in males and 12.9+/-1.8 microg/l in females (P<0.05). After 2 years of BC treatment, prolactin levels were near normal (males: 665+/-439 mU/l, females 447+/-130 mU/l; P<0.05) and BMI remained 26.5+/-1.9 kg/m(2) for males and 23.6+/-0.8 kg/m(2) for females (P<0.05). Leptin levels were 9.5+/-2.2 microg/l in males and 18.7+/-3.1 microg/l in females (P<0.05). There was a gradual increase in the gender difference in serum leptin levels over time. Changes in serum leptin levels significantly correlated with changes in BMI (r=0.844, P<0.001) but did not correlate with changes in plasma prolactin levels after 1 month (r=0.166), 6 months (r=0.313) and 2 years (r=0.234, P>0.05). CONCLUSION: The long-acting dopamine agonist BC, by increasing dopaminergic tone, may influence body weight and likely body composition by mechanisms in addition to reducing hyperprolactinemia in patients with prolactinomas.

Adolescent↗

PubMed2002

Ghrelin-induced GH secretion in normal subjects is partially resistant to homologous desensitization by GH-releasing peptide-6.

OBJECTIVE: GH secretagogues and GH-releasing hormone (GHRH) exert a complex cross-talk at the somatotrope cell, and undertake homologous and heterologous desensitization. On the other hand, the discovery of ghrelin as a new factor implicated in the regulation of GH secretion makes a thorough assessment of its properties and cell biology processes mandatory. In order to implement this, three different testing schedules were devised using the administration, on the same day, of two GH stimuli administered in sequential order 120 min apart. The two aims of the study were (a) to evaluate the relative potency of ghrelin in comparison with other GH stimulants and (b) to assess the presence of homologous or heterologous desensitization between these compounds. DESIGN: The different testing days performed in random order were (a) on one day, saline was administered at time 0 min and ghrelin at time 120 min, (b) on another testing day, GHRH was administered at 0 min followed by ghrelin at 120 min and (c) on the last testing day, GH-releasing peptide-6 (GHRP-6) and ghrelin were injected at 0 and 120 min respectively. Ghrelin, GHRH and GHRP-6 were always administered at 1 microg/kg i.v., and plasma GH was measured. PATIENTS: Six normal subjects participated in the study after providing informed consent, and each was assessed on three different testing days, at least 1 week apart. RESULTS: Saline did not modify peak GH (means+/-s.e.) values (1.5+/-0.6 microg/l), and ghrelin administered 120 min later induced a significant GH rise (39.9+/-2.8 microg/l). On a different testing day, GHRH induced a GH peak (9.4+/-2.8 microg/l) lower than that of ghrelin injected 120 min later (26.8+/-4.7 microg/l). On the last testing day, GHRP-6 at time 0 induced a GH peak of 18.4+/-5.9 microg/l and ghrelin 120 min later a peak of 19.8+/-2.9 microg/l. The ghrelin-mediated GH secretion after GHRP-6 was significantly lower than the GH elicited by ghrelin when the preceding administration was saline. This demonstrated that ghrelin was partially affected by GHRP-6 and was not affected by GHRH. CONCLUSIONS: Calculated at equal mass doses or in molecular terms, ghrelin appears to be a more potent stimulus than GHRP-6 and GHRH. Ghrelin was completely insensitive to the previous administration of GHRH as well as relatively resistant to the homologous desensitization exerted by GHRP-6.

Adult↗

PubMedDate not supplied

The influence of serum cortisol levels on growth hormone responsiveness to GH-releasing hormone plus GH-releasing peptide-6 in patients with hypocortisolism.

The aim of this study was to evaluate the influence of circulating cortisol levels on the somatotroph responsiveness to the most potent stimuli of growth hormone (GH) secretion, the GHRH+GHRP-6 test. We studied 12 patients with hypocortisolism (10 with Addison's disease and 2 with isolated ACTH deficiency) before and after glucocorticoid (GC) replacement therapy and compared them with 14 healthy subjects. In the 10 patients with Addison's disease, GH responses (GH peak, microg/L) to GHRH+GHRP-6 were similar both during GC, (68.2+/-12.8) and off GC (60.3+/-14.1) therapy and did not differ from those in controls (61.5+/-6.0). In a subgroup of 4 patients with newly diagnosed Addison's disease, GH responsiveness to GHRH+GHRP-6 prior to GC replacement (26.4+/-4.1) was significantly lower than in the 6 patients with long-standing Addison's disease after short-term GC withdrawal (82.9+/-18.2). In the newly diagnosed Addison's patients, after one month of GC replacement, mean GH peak value increased to 40.7+/-11.8. In the 2 patients with isolated ACTH deficiency, GH responses to GHRH+GHRP-6 did not differ off and on GC therapy (60.3+/-14.1 and 41.5+/-2.0, respectively). Our data suggest that short-term GC deprivation does not have a major impact on GH responsiveness to GHRH+GHRP-6. However, in patients with long-standing hypocortisolism, GH response is blunted but still within normal range (> 15 microg/L).

Journal Article↗