Sex-based differences in serum leptin concentrations have been reported in adolescence and adulthood. To discover when such differences were generated, serum leptin concentrations were measured in umbilical cord blood from 46 healthy infants and in the mother's blood at delivery. Considering the respective body weights of the mothers and infants (68.5 +/- 1.3 kg and 3.3 +/- 0.0 kg), umbilical cord concentrations of leptin were disproportionately high in the infants (9.4 +/- 1.2 micrograms/l) compared with those in the mothers (18.7 +/- 1.3 micrograms/l). There was a wide variation in the infants leptin values (1.2 +/- 56.8 micrograms/l) that did not correlate with height, weight, cephalic circumference, or any other growth-related parameter. The most striking differences emerged when results were analysed by sex: umbilical cord concentrations of leptin in the girls (12.9 +/- 2.2 micrograms/l) were significantly (P < 0.01) greater than those in the boys (6.8 +/- 0.9 micrograms/l), although no differences in leptin concentrations were observed between the mothers who gave birth to a girl (19.5 +/- 2.2 micrograms/l) and those who gave birth to a boy (18.1 +/- 1.7 micrograms/l). The sex-based differences were not attributable to any growth-related differences between the sexes, except heavier placental weights in the girls (P < 0.007) than in the boys. These differences in leptin concentrations may reflect a sex-based difference in the regulation of leptin production by the fetal adipose tissue.
MA Tome, M Lage, JP Camina, RV Garcia-Mayor, C Dieguez, and FF Casanueva
W Kiess, M Anil, WF Blum, P Englaro, A Juul, A Attanasio, J Dotsch, and W Rascher
The ob protein, termed leptin, is produced by adipocytes and is thought to act as an afferent satiety signal regulating weight through suppressing appetite and stimulating energy expenditure in humans and/or rodents. Insulin has been found to be a potent stimulator of leptin expression in rodents. It is unclear at present whether this insulin action is a direct or an indirect effect. To investigate whether leptin concentrations in children and adolescents with type 1 diabetes (IDDM) were related to metabolic status, body weight, body mass index and insulin treatment, we have measured leptin concentrations in serum from 13 newly diagnosed IDDM patients before the beginning of insulin treatment (8 girls, 5 boys, aged 4.7-17.5 years) and in 134 patients with IDDM during treatment (64 girls, 70 boys, aged 2.6-20.1 years) using a specific radioimmunoassay. The data from patients with diabetes were compared with normative data that were derived from a large cohort of healthy children and adolescents. Serum from children with newly diagnosed diabetes had significantly lower levels of leptin (mean 1.28+/-1.60 ng/ml, range 0.14-6.13 ng/ml) compared with healthy children (n=710) (mean 2.2 ng/ml, range 0.26-14.4ng/ml) and compared with insulin-treated children and adolescents (mean 5.18+/-5.48 ng/ml, range 0.26-29.77 ng/ml) (P<0.0001) even after adjustment for gender and body mass index (BMI). Serum leptin levels in patients with IDDM were significantly correlated with BMI (r=0.42, P<0.0001). Multiple regression analysis showed that age and BMI were significantly correlated with leptin levels, while duration of diabetes, mean HbA1c levels, insulin dose and plasma glucose, triglyceride and cholesterol levels were not. Females had higher serum leptin concentrations than males even when adjusted for BMI (P<0.0001). Surprisingly and most importantly, leptin levels in insulin-treated young adult (Tanner stage 5) patients were significantly higher than values found in the healthy nondiabetic reference population when adjusted for sex, Tanner stage and BMI. These findings suggest that leptin levels in IDDM patients show a similar dependency on adipose tissue and age as in healthy, normal children. The data provide evidence that insulin may be of importance as a regulator of serum leptin levels in vivo not only in rodents but also in humans. It is hypothesized that the elevated BMI-adjusted leptin levels in adolescents with IDDM could indicate either that these patients may be oversubstituted by the intensified insulin therapy that they are receiving or that their body composition and body fat content may differ from that of healthy adolescents in the sense that they have a relative increase in fat mass.
C Bouvattier, N Lahlou, M Roger, and P Bougneres
In ob/ob mice, leptin deficiency results in hypogonadotrophic hypogonadism, impaired sexual maturation and infertility, which are all corrected by leptin administration. In humans, pubertal development and menarche are related to the attainment of a critical amount of body fat. To examine whether changes in circulating concentrations of leptin could be a hormonal signal influencing gonadotrophin secretion, we studied 98 adolescents and young adults of both sexes, aged 13-19 years, whose weight varied from normal to massively obese and whose sexual maturation was between Tanner stages 3 and 5. We measured leptin, sex steroids and circulating gonadotrophin concentrations in the basal state and in response to GnRH. In perimenarchial and young adult girls, we found that the LH and FSH responses to GnRH were negatively correlated with body mass index (BMI: r = -0.45 and -0.47 respectively, P < 0.0025) and circulating leptin (r = -0.53 and -0.49 respectively, P < 0.002). Decreased LH and FSH responses to GnRH were associated with increased adiposity and hyperleptinaemia. Our data do not establish, but are consistent with a direct neuroendocrine negative effect of excess leptin on the central reproductive system of obese girls. In boys of comparable adiposity, we found no influence of BMI or leptin on gonadotrophin concentrations, which is another aspect of the sexual dimorphism characterizing human leptin physiology.
In recent years, it became evident that the hypothalamo-pituitary-gonadal axis is functioning in boys already between the neonatal period and the onset of puberty. With sensitive techniques, testosterone and gonadotropines have been detected in the plasma and urine of prepubertal boys. It is now believed that, during this period of life, the axis is active, but that either the feedback mechanisms are adjusted to a different level, the hypothalamic centers being more sensitive to androgens and keeping the testicular androgen production low, or that the gonads are more refractory to the effect of gonadotropins.
The androgen levels in biological fluids from normal prepubertal boys are extremely low. It is therefore impossible to distinguish the basal values of children with defective steroid production from those of normal children. Recently, several investigators have, however, shown that stimulation of the testicular interstitial cells is possible, if human chorionic gonadotropin is administered for several
Klemens Raile, Michele O'Connell, Angela Galler, George Werther, Peter Kühnen, Heiko Krude, and Oliver Blankenstein
Mutations of the preproinsulin gene (INS) account for both permanent neonatal diabetes (PND) and adult-onset diabetes. The molecular mechanism of complete INS deletion has recently been published and we now add clinical data of homozygous and heterozygous subjects as well as the detailed mapping of the 646 bp deletion of the INS gene.
Location and size of the INS deletion was mapped in one case with PND and INS genotype of the whole family was further characterized by breakpoint-spanning PCR. The phenotype of monoallelic loss of INS was studied in 33 adult family members of a large consanguineous kindred with INS deletion.
The 646 bp deletion was found in two individuals with PND that included exons 1 and 2 of the INS gene (chr11: g.2138434_2139080del646) and results in loss of approximately half of the preproinsulin protein. The two boys with homozygous INS deletion (D/D) presented with reduced birth weight, PND within the first 24 h of life and complete absence of C-peptide. Adult family members with the N/D had diabetes onset with earliest 25 years, while the oldest subject without diabetes was 45 years. INS-deletion-diabetes was initially treated with oral antidiabetic drugs but then transferred to insulin within 5–16 years. Overall, N/D-subjects (n=11) had a higher risk to develop insulin-dependent diabetes up to the fifth decade, if compared with normal subjects (n=22).
Complete loss of the human INS gene results in neonatal diabetes, while heterozygous INS deletion is a strong risk factor for developing insulin-dependent diabetes at adult age.
Anna Nordenström and Henrik Falhammar
Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted.
E. Artavia-Loria, J.L. Chaussain, P.F. Bougnères, and J.C. Job
The frequency of hypoglycemia in 165 children with primary adrenal insufficiency, 118 of whom had Congenital Adrenal Hyperplasia and 47 Addison's Disease, was 18 %. Half of the hypoglycemic episodes occurred in the neonatal period. Hypoglycemia was isolated in 13 children, revealing the disease in 4 newborns with Congenital Adrenal Hypoplasia and in a boy with 11 B Hydroxylase deficiency.
Basal plasma cortisol levels were significantly lower in those of subjects who experienced hypoglycemia ( 47.1 ± 28.6 ng/ml vs. 106.0 ± 86.6 ng/ml, p< 0.001). A significant correlation ( p < 0.001) was found between the plasma concentration of glucose and cortisol at time of hypoglycemia.
Sylvie Hiéronimus, Magali Bec-Roche, Florence Pedeutour, Jean Claude Lambert, Kathy Wagner-Malher, Jean Christophe Mas, Jean Louis Sadoul, and Patrick Fénichel
Objective: Clinical features associated with microdeletion of chromosome 22q11 (del(22)(q11)) are highly variable. Increased awareness of this condition is needed among specialists such as endocrinologists to reduce diagnostic delay and improve clinical care. The purpose of this study was to describe the phenotype of patients with del(22)(q11), focusing on parathyroid gland dysfunction.
Design and methods: Charts of 19 patients, including one kindred of three, known to have del(22)(q11) diagnosed by fluorescence in situ hybridization (FISH) were reviewed from the register of the department of Medical Genetics. Major clinical features including hypoparathyroidism phenotype were collected.
Results: Parathyroid dysfunction was present in 8 out of 16 patients (50%). Six patients were diagnosed with overt hypoparathyroidism. Hypocalcemia manifested as laryngeal stridor within the first days of life (n=3), seizures in infancy (n=1) and adolescence (n=2). The connection between hypoparathyroidism and diagnosis of del(22)(q11) was belated at the median age of 18 years. One patient had presented with transient neonatal hypoparathyroidism, and one patient had latent hypoparathyroidism. Within the kindred family, the phenotype variability including that of parathyroid dysfunction was as marked as between unrelated individuals. Standard karyotype failed to detect the deletion in 15 out of 19 cases.
Conclusions: Abnormal parathyroid function in the del(22)(q11) ranges from severe neonatal hypocalcemia to latent hypoparathyroidism. Del(22)(q11) should be considered as a potential cause of hypocalcemia even in young adult. When suspected, the diagnosis requires investigation by FISH. Furthermore, long-term calcemia follow-up is needed in normocalcemic patients with del(22)(q11) because of the possible evolution to hypocalcemic hypoparathyroidism.
H Schmidt and HP Schwarz
OBJECTIVE: A sex difference in fetal and neonatal pituitary-gonadal function has been well documented. The aim of the following study was to determine sex differences and patterns of basal LH/FSH in the neonatal period. DESIGN: Peripheral venous blood was obtained from 164 healthy full term newborns (91 males, 73 females) for clinically indicated laboratory examinations. RESULTS: In male newborns, LH values were initially low (days 1-5), increased between days 6 and 10, and reached maximum levels between days 16 and 20. Levels of FSH were initially low (days 1-5), increased between days 6 and 10 and reached maximum levels between days 11 and 15. In female newborns, LH levels were generally lower than in newborn boys; levels were initially low, then increased between days 11 and 15 and reached maximum levels at the end of the newborn period. FSH values were generally higher than in newborn boys; there were initially low values with a first peak between days 11 and 15 and a second peak between days 21 and 28. CONCLUSIONS: LH values in male newborns were higher and exceeded values in female newborns, whereas FSH values in female newborns exceeded male newborn values. Male newborns do not exhibit any peaks of LH and FSH activity, whereas female newborns exhibit two FSH peaks during this period.
J Pohlenz, W Ahrens, and O Hiort
OBJECTIVE: To identify the molecular defect by which psychomotor retardation is caused in two brothers with congenital hypothyroidism who received adequate treatment with l-thyroxine. CASE REPORT: A six-year-old boy presented with psychomotor retardation and congenital primary hypothyroidism (CH). The patient had a normal blood thyrotrophin (TSH) level on neonatal screening, but low total serum thyroxine and triiodothyronine concentrations prompting thyroid hormone substitution shortly after birth. Nevertheless, psychomotor development was retarded and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO) such as round face, obesity, and shortened 1st, 4th and 5th metacarpals were found. METHODS AND RESULTS: Further investigation confirmed AHO with pseudohypoparathyroidism (PHP) type Ia. The boy had a mild resistance to parathyroid hormone and a reduced adenylyl cyclase stimulating protein (Gsalpha) activity in erythrocytes. DNA analysis detected a new heterozygous mutation (L338N) in the Gsalpha protein (GNAS1) gene. This mutation was also present in the patient's brother who had similar features and was also treated with thyroid hormone because of CH, and in the phenotypically normal-looking mother who had a normal calcium metabolism but a reduced Gsalpha protein activity in erythrocytes suggestive of pseudopseudohypoparathyroidism. CONCLUSION: In patients with CH, in whom the neurological outcome is poor even under adequate thyroid hormone substitution, PHP Ia may be suspected, especially when symptoms of AHO are present.