Anorexia nervosa (AN) is a chronic childhood psychiatric illness that involves a reduction in caloric intake, loss of weight and amenorrhea, either primary or secondary. The diagnostic criteria for AN have been established by the American Psychiatric Association. The prevalence of this disease amongst adolescents and young adults is between 0.5 and 1% and the incidence of new cases per year is approximately 5-10/100,000 between 15 and 19 years of age.A number of endocrine and metabolic disturbances have been described in patients with AN including amenorrhea-oligomenorrhea, delayed puberty, hypothyroidism, hypercortisolism, IGF-I deficiency, electrolyte abnormalities, hypoglycemia and hypophosphatemia, among others. In addition to prolonged amenorrhea, osteopenia and osteoporosis are the most frequent complications leading to clinically relevant fractures and increased fracture risk throughout life. Patients exhibit an alteration in the hypothalamic-pituitary-gonadal axis, which is responsible for the menstrual disorders. The increase in gonadotropin secretion that can be observed after ponderal recuperation suggests that malnutrition could be the most important mechanism involved in the decrease in gonadotropin secretion.The loss of fat tissue as a consequence of nutrient restriction has been associated with hypoleptinemia and abnormal secretion of peptides implicated in food control (neuropeptide Y, melanocortins and corticotropin-releasing factor, among others).A review of the endocrine abnormalities, disturbances in neurotransmitters, as well as a detailed analysis of bone markers and bone mineral density in patients with AN is described.
MT Munoz and J Argente
JA Chowen, LM Frago and J Argente
Gonadal sex steroids modulate GH synthesis and secretion with effects on both the hypothalamus and anterior pituitary. In the post-pubertal animal, androgens and oestrogens modulate hypothalamic somatostatin (SS) and GHRH synthesis respectively. These effects may be direct as SS neurons express the androgen receptor and many GHRH neurons are oestrogen receptor positive. The neonatal steroid environment modulates the number of GHRH neurons in the adult hypothalamus, as well as their responsivity to post-pubertal steroids. Furthermore, both neonatal and post-pubertal steroids modulate hypothalamic synaptic organisation affecting the number of synaptic inputs and the morphology of glial cells. This in turn has important effects on the ability of the hypothalamus to drive the secretory pulsatility of anterior pituitary hormone release. At the level of the somatotroph, androgens and oestrogens have been reported to stimulate, inhibit or have no effect on GH synthesis. In primary cultures, we found no effect of either androgens or oestrogens on GH mRNA levels. However, the sex steroid environment significantly modified the response of somatotrophs to SS. Furthermore, males have more somatotrophs compared with female rats and this partially depends on the neonatal sex steroid environment. In conclusion, sex steroids have both organisational and activational effects on the GH axis. These effects range from modulating the number of hypothalamic neurons controlling GH secretion, their responsiveness to later steroids, and the synaptic connectivity and neuropeptide production, to modulation of somatotroph numbers in the anterior pituitary and their responsiveness to inputs controlling GH synthesis and secretion.
B Arguelles, V Barrios, M Buno, L Madero and J Argente
OBJECTIVE: The aim of this study was to follow auxological parameters and their relationship to serum growth hormone-binding protein (GHBP) and leptin levels in children with acute lymphoblastic leukemia (ALL). DESIGN AND METHODS: In total, 26 prepubertal children with ALL were studied. We report these data at the time of the clinical diagnosis (n=26) and at 6 (n=21), 12 (n=21), 18 (n=21), 24 (n=20), 30 (n=16) and 36 months (n=16) after beginning treatment. RESULTS: Serum GHBP levels decreased during the first 18 months and returned to normal when therapy was withdrawn. Height SDS increased at 24 months after diagnosis. Weight and the upper arm circumference had increased 6 months after chemotherapy withdrawal, whereas tricipital and subscapular skinfolds had increased both at 6 months after diagnosis and 6 months after therapy had stopped. Therefore, the tendency to become overweight is both an early and a late side-effect of anti-leukemia therapy. A significant positive correlation was found between serum leptin levels and every nutritional anthropometric parameter, with body mass index having the best relationship. However, serum GHBP levels were only correlated with BMI at the end of the study. No correlation was found between leptin and GHBP. CONCLUSIONS: In children with ALL, linear growth is compromised during the acute phase of their illness and therapy; this is probably secondary to a state of partial and transient GH insensitivity. These patients tend to become obese after therapy withdrawal, with leptin being an excellent nutritional marker.
MT Munoz, G Morande, JA Garcia-Centenera, F Hervas, J Pozo and J Argente
OBJECTIVE: Profound osteopenia is a serious complication of anorexia nervosa (AN). The aim of this work was to study the effect of prolonged AN on lumbar spine bone mineral density (BMD) and to determine whether oral estrogen administration prevents bone loss in women with this disorder. SUBJECTS AND METHODS: Thirty-eight amenorrheic women with AN (mean age: 17.3 years) were treated with estrogen (50 microg of ethinyl estradiol) and gestagen (0.5 mg of norgestrel) during 1 year. Clinical variations, biochemical indices and BMD were studied at three different time points, including after a period of amenorrhea of at least 12 months (n=38), after the administration of estrogens for 1 year (n=22), and after a 1-year follow-up period (n=12). RESULTS: Initial mean BMD was significantly lower than normal (-2.1+/-0.8 s.d.) and less than -2.5 s.d. below normal in 38% of the women with AN. The estrogen-treated group had no significant change in BMD even after the follow-up period and partial recovery of weight. Estradiol and total IGF-I levels were significantly lower throughout the study. All subjects had normal thyroxine (T(4)) and TSH levels and calcium metabolism. However, total tri-iodothyronine (T(3)) was decreased in all anorexic subjects in the first and second study points and were within normal limits after the follow-up period. CONCLUSIONS: (1) Estrogen replacement alone cannot prevent progressive osteopenia in young women with AN. (2) Other factors, such as the loss of weight, the duration of the amenorrhea and the low levels of total insulin-like growth factor-I (IGF-I) could contribute to the loss of bone mass in women with this disorder.
V Barrios, J Argente, MT Munoz, J Pozo, JA Chowen and M Hernandez
OBJECTIVE: To analyze the possible utility of measuring acid-labile subunit (ALS) in some types of pathologies in which the IGF system is altered and to compare it with the clinical implications of measurements of other components of this axis. DESIGN AND METHODS: We studied serum ALS concentrations in 20 children with normal variants of short stature (NVSS) at diagnosis and 24 with growth hormone deficiency (GHD), 18 obese patients and 18 girls with anorexia nervosa at diagnosis and during a follow-up period. RESULTS: In patients with GHD and anorexia nervosa, mean ALS concentrations were significantly reduced, but there was a high percentage of overlap with control values. At diagnosis, ALS concentrations were normal in obese patients and children with NVSS. During follow-up, these values normalized in children with GHD who were treated with GH, tended to normalize in those with anorexia nervosa who showed weight gain, and did not change in obese children upon weight loss. However, ALS measurement was less accurate than that of IGF-I or IGF binding protein (IGFBP)-3 in diagnosis of GHD. The correlations found between ALS and some IGF system components at diagnosis either decreased or were non-significant during follow-up of these clinical conditions. CONCLUSION: ALS adds little information to that obtained with IGF-I and IGFBP-3 determinations.
C. Liapi, D. Evain Brion, J. Argente, H. Vaudry and M. Donnadieu
Abstract. On forty-six fasting and resting children, aged 5–17 years, with short stature (below −2 sd) a growth hormone releasing hormone (GH-RH) stimulation test (2 μg/kg iv bolus, Sanofi) was performed. Twenty-two children were prepubertal, of which, 13 had a constitutional short stature (CSS), nine an idiopathic growth hormone deficiency (IGHD). Twenty-four subjects were pubertal, at the stage II or III of Tanner. Among them, six had a constitutional short stature (CSS) and 18 an idiopathic delayed puberty (IDP). Blood samples were taken for determination of plasma somatostatin-like immunoreactivity (SLI) in chilled test tubes containing EDTA + aprotinin. Plasma SLI levels were measured after extraction and concentration on C 18 Sep Pack columns by radioimmunoassay using an antibody against 1–14 somatostatin. The sensitivity of this assay is around 3 pg/ml. After GH-RH stimulation the peak of GH (mean ± sem) was in prepubertal subjects: 25.3 ± 9.1 μg/l in CSS, and 18.6 ± 10.3 μg/l in IGHD. In pubertal subjects GH peaks were 17.6 ± 8.4 μg/l in CSS and 15.6 ± 3.8 μg/l in children with IDP. No significant differences was found between basal plasma SLI levels in the four groups of subjects, being respectively (mean ± sem) 11.9 ± 1.8 pg/ml in prepubertal subjects with CSS, 9.6 ± 2.6 pg/ml in IGHD, 7.6 ± 1.7 pg/ml in pubertal children with CSS and 6.6 ± 1.5 pg/ml in children with IDP. However, in the 46 children, a significant (r = −0.524, P < 0.001) negative correlation was found between the amplitude of the peak of serum GH after GH-RH injection, and the basal values of SLI. The results suggest a possible regulatory mechanism for circulating somatostatin on GH release after injection of GH-RH.
L Goya, LM Garcia-Segura, S Ramos, AM Pascual-Leone, J Argente, MA Martin and JA Chowen
OBJECTIVE: In malnutrition both the GH-IGF and reproductive axes are greatly affected. Because the actions of IGF and sex steroids are inter-dependent in many tissues, we have examined how ovariectomy modulates the response of the systemic IGF system to undernutrition. DESIGN AND METHODS: Peripubertal (30 days of age) female rats were either sham operated or ovariectomized. Five days later half of each group was submitted to a protein-caloric restriction diet. All rats were killed at 60 days of age. RESULTS: Growth was decreased in all rats submitted to calorie restriction and this was consistent with a decrease in circulating IGF-I concentrations and liver IGF-I mRNA expression. While in normally fed rats ovariectomy had no significant effect on serum IGF-I concentrations, ovariectomized and underfed rats had significantly higher levels than intact underfed rats. In undernourished rats, serum IGF-binding proteins (IGFBP)-1, -2 and -3 concentrations were significantly reduced and this was not modified by ovariectomy. In contrast, liver mRNA concentrations of IGFBP-1 and -2 were increased and IGFBP-3 unchanged in intact undernourished animals, suggesting that undernutrition could be affecting the proteolysis of these binding proteins, and this response was significantly modulated by ovariectomy. CONCLUSION: These results indicate that the presence of circulating ovarian hormones significantly affects the response of the IGF system to undernutrition.
L Soriano-Guillen, V Barrios, G Martos, JA Chowen, A Campos-Barros and J Argente
OBJECTIVE: Coexpression of GH secretagogue receptor and ghrelin in the pancreas suggests that this peptide is involved in glucose metabolism. Previous reports in adult humans have demonstrated that plasma ghrelin levels decrease after oral glucose administration. However, no data are available in children. Therefore, the aim of this study was to analyze the response of plasma ghrelin levels in obese children after oral glucose administration. SUBJECTS AND METHODS: Twenty-eight obese children ranging from Tanner I to Tanner V were studied. All subjects were given 0.75 g/kg (maximum 75 g) glucose solution after overnight fasting. Ghrelin, insulin, glucose and IGF-binding-protein-1 were determined at 0, 30, 60 and 120 min of the oral glucose tolerance test (OGTT). RESULTS: Basal plasma ghrelin levels were significantly lower than in the respective control groups. These levels decreased significantly during OGTT in obese children, reaching a nadir of 28+/-9% at 60 min in parallel with the maximum increase in glucose levels and previous to maximum insulin levels. CONCLUSION: The rapid fall in plasma ghrelin concentration in obese children after glucose load suggests a mechanism for the control of appetite after food intake.
MT Munoz, C de la Piedra, V Barrios, G Garrido and J Argente
OBJECTIVE: Our aim was to compare physical activity and biochemical markers with bone mineral acquisition in rhythmic gymnasts and ballet dancers. METHODS: Weight, height, body mass index, nutritional intake, bone age and menstrual histories were analyzed in nine rhythmic gymnasts, twelve ballet dancers and fourteen controls. Bone mineral density (BMD) was assessed by X-ray absorptiometry at the lumbar spine, hip and radius. Bone alkaline phosphatase (bAP) and amino-terminal propeptide of procollagen I (PNIP) in serum and urinary alpha-isomer of the carboxy-terminal telopeptide of collagen I (alpha-CTX) were measured. RESULTS: Bone age was delayed 2 years and mean age at menarche was 15+/-0.9 years in rhythmic gymnasts and 13.7+/-1 years in ballet dancers, compared with 12.5+/-1 years in controls. Trocanteric and femoral neck BMD was significantly higher in rhythmic gymnasts compared with ballet dancers and controls. Right forearm (non-loaded zone) BMD was significantly decreased in rhythmic gymnasts and ballet dancers compared with controls. All subjects had normal bAP and PNIP levels, but the alpha-CTX/creatinine (Cr) ratio was increased in rhythmic gymnasts (P<0.001) with an inverse correlation between right forearm BMD and the alpha-CTX/Cr ratio (r=-0.74, P<0.001). Serum leptin levels were decreased in rhythmic gymnasts and ballet dancers. Rhythmic gymnasts had a positive correlation between right forearm BMD and leptin levels (r=0.85, P<0.001). CONCLUSIONS: Decreased bone mass in rhythmic gymnasts could be partially explained by an increase in bone resorption. Serum leptin levels could be implicated in the pubertal delay and be a good marker of bone mass in these subjects.
M A Donoso, M T Muñoz-Calvo, V Barrios, G Garrido, F Hawkins and J Argente
Ballet dancers (BDs) have a negative energy balance related to physical training that results in alterations in body composition, sexual development, and adipokine secretion. Our aims were to study anthropometric parameters, body composition, and their relationship with adipokines throughout pubertal development.
Subjects and methods
We carried out a prospective follow-up study of 22 female Caucasian BDs (Tanner II stage) followed throughout puberty. Nutritional status was determined by measurement of height, weight, and body mass index (BMI). We calculated growth velocity, bone maturity, and body composition at Tanner stages II, III, and V by dual energy X-ray absorptiometry. Circulating leptin, adiponectin, and soluble leptin receptor (sObR) levels were determined.
BDs presented a delay in skeletal maturation during puberty, without affectation of final height. Energy intake was deficient according to their physical exercise, and they had a delay of 1 year in the mean age of menarche. Leptin levels were decreased, whereas sObR and adiponectin levels were increased throughout puberty. The percentage of trunk fat, total fat mass, and fat of the extremities was decreased throughout the study period (P<0.01). Lean mass was increased in the lower extremities, and bone mineral density was normal.
A negative energy balance together with maintained physical exercise induced modifications in body composition in BDs. Changes in leptin and adiponectin levels appear to be more related to total fat content than to BMI. Furthermore, the onset and delayed progress of puberty may be related with an inadequate energy balance due to increased exercise.