Najiba Lahlou

A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction

The adipocyte-specific hormone leptin, the product of the obese (ob) gene,regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations ingenes encoding leptin or the leptin receptor cause early-onsetmorbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadism. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.

Oral insulin administration and residual (β-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial

Summary Background Oral administration of autoantigens can slow the progression of β-cell destruction in non-obese diabetic mice. We investigated whether oral administration of recombinant human insulin could protect residual β-cell function in recent-onset type 1 diabetes. Methods We enrolled 131 autoantibody-positive diabetic patients aged 7–40 years within 2 weeks of diagnosis (no ketoacidosis at diagnosis, weight loss Findings Baseline C-peptide and haemoglobin A lc concentrations were similar in the three groups. During follow-up, there were no differences between the groups assigned 2·5 mg or 7·5 mg oral insulin or placebo in subcutaneous insulin requirements, haemoglobin A lc concentrations, or measurements of fasting (mean at 12 months 0·18 [SD 0·17], 0·17 [0·17], and 0·17 [0·12] nmol/L) or stimulated C-peptide concentrations (glucagon-stimulated 0·39 [0·38], 0·37 [0·39], and 0·33 [0·24] nmol/L; meal-stimulated 0·72 [0·60], 0·49 [0·49], and 0·57 [0·51 nmol/L]. Neither age nor C-peptide concentration at entry influenced treatment effects. No differences were seen in the time-course or titres of antibodies to insulin, glutamic acid decarboxylase, or islet antigen 2. Interpretation At the doses used in this trial, oral administration of insulin initiated at clinical onset of type 1 diabetes did not prevent the deterioration of β-cell function.

A polymorphism in the 5′ untranslated region of the human ob gene is associated with low leptin levels

OBJECTIVE: To search the human ob gene for mutations and evaluate their role in massive obesity.DESIGN: Direct mutation screening of the gene and case-control association study. Multivariate analyses for evaluation of differences in clinical parameters.SUBJECTS: Primary mutation screening: 24 morbidly obese subjects (body mass index (BMI) >40 kg/m2). Association study: 395 unrelated morbidly obese subjects (BMI >40 kg/m2), 121 lean, non-diabetic control individuals, 72 women of a random sample with an average BMI 32.5 kg/m2.RESULTS: We report the finding of a DNA variant in exon 1 of the human ob gene (A−>G substitution, base +19). This variant showed a prevalence of 62% in our study population. Association analyses under different genetic models (dominant, co-dominant, recessive) showed no significant evidence for an association of this variant with BMI. However, obese individuals homozygous for the G-allele showed significantly lower leptin concentrations compared to obese patients either heterozygous or homozygous for the A-allele after correction for BMI.CONCLUSION: Recent linkage studies have shown evidence for linkage of the hsob locus with obesity. Our study provides further evidence that a defect in the ob gene in linkage disequilibrium with the G-allele of exon 1 might be involved in obesity by affecting leptin concentrations.

Antimüllerian hormone as a serum marker of granulosa cell tumors of the ovary: Comparative study with serum α-inhibin and estradiol ☆ ☆☆ ★ ★★

OBJECTIVE Our purpose was to evaluate serum antimüllerian hormone as a marker for granulosa cell tumors. STUDY DESIGN Serum antimüllerian hormone concentrations were determined in 16 patients with an adult-type granulosa cell tumor; in female patients with ovarian adenocarcinoma, benign ovarian cysts, or extraovarian cancers; and in normal premenopausal and postmenopausal women. Serum antimüllerian hormone, alpha-inhibin, and estradiol levels were compared in 10 patients with a granulosa cell tumor during 6 to 47 months of follow-up. RESULTS Serum antimüllerian hormone was undetectable in normal postmenopausal women and was <5 micrograms/L in premenopausal women. Normal serum levels were found in patients with ovarian cancers or cysts or with extraovarian cancers. Levels were between 6.8 and 117.9 microg/L in eight of nine patients with a progressive granulosa cell tumor. In the remaining case antimüllerian hormone, alpha-inhibin and estradiol concentrations were normal. Serum antimüllerian hormone and alpha-inhibin levels became elevated at least 11 months before the recurrence was clinically detectable. During clinical remission serum antimullerian hormone, beta-inhibin, and estradiol were normal in most cases. CONCLUSION Serum antimüllerian hormone is a sensitive, specific, reliable marker of adult-type granulosa cell tumors and is useful to evaluate the efficacy of treatment and to detect recurrences early.

Early androgen deficiency in infants and young boys with 47,XXY Klinefelter syndrome.

Background/Aims: Klinefelter syndrome (KS) is characterized by the karyotype 47,XXY. In this study, we evaluated the physical and testicular failure phenotypes of infants and young boys with KS. Methods: The evaluation included auxologic measurements, biologic indices of testicular function, and clinical assessment of muscle tone in 22 infants and young boys with KS, ages 1–23 months. Results: Mean length, weight, and head circumference in SDS were generally within the normal range at –0.3 ± 1.0, –0.1 ± 1.4, and 0.0 ± 1.5, respectively. Mean penile length and testicular volume SDS were –0.9 ± 0.8 and –1.1 ± 0.8, indicating significantly reduced penile and testicular size. Mean testosterone levels for the boys ≤6 and >6–23 months were 128 ± 131 (4.4 ± 4.5 nmol/l) and 9.5 ± 7.2 ng/dl (0.3 ± 0.2 nmol/l), respectively. High-arched palate was observed in 6/17 boys and clinodactyly (5th finger) was observed in 15/16 boys. Hypotonia was evaluated clinically and was noted to be present in 12/17 boys. Conclusion: The physical phenotype in infants and young boys with KS (1–23 months old) includes normal auxologic measurements and early evidence of testicular failure. Muscle tone was decreased in most of the boys. Testicular volume and penile length were diminished, indicating early androgen deficiency. The neonatal surge in testosterone was attenuated in our KS population. Thus, infants and young boys with KS have evidence of early testicular failure. The etiology of this failure and the clinical role of early androgen replacement require further study.

Effect of Ascertainment and Genetic Features on the Phenotype of Klinefelter Syndrome

OBJECTIVE To describe the Klinefelter Syndrome (KS) phenotype during childhood in a large cohort. STUDY DESIGN Clinical assessment, measurement of hormonal indices of testicular function, and parent of origin of extra X chromosome were assessed in a cross-sectional study of 55 boys with KS, aged 2.0 to 14.6 years, at an outpatient center. RESULTS Mean height and body mass index SD scores (SDS +/- SD) were 0.9 +/- 1.3 and 0.4 +/- 1.4, respectively. Mean penile length and testicular volume SDS were -0.5 +/- 0.9 and -0.9 +/- 1.4. Testosterone levels were in the lowest quartile of normal in 66% of the cohort. Other features included clinodactyly (74%), hypertelorism (69%), elbow dysplasia (36%), high-arched palate (37%), hypotonia (76%), and requirement for speech therapy (69%). Features were similar in boys in whom the diagnosis was made prenatally versus boys in whom the diagnosis was made postnatally. There was no evidence for a phenotypic effect of parent of origin of the extra X chromosome. CONCLUSIONS Boys with KS commonly have reduced penile length and small testes in childhood. The phenotype in boys with KS does not differ according to ascertainment or origin of the extra X chromosome. Boys with KS may be identified before puberty by tall stature, relatively decreased penile length, clinodactyly, hypotonia, and requirement for speech therapy.

Cotreatment with growth hormone for induction of spermatogenesis in patients with hypogonadotropic hypogonadism

Objective To induce spermatogenesis by cotreatment with growth hormone (GH) and gonadotropin therapy in patients with hypogonadotropic hypogonadism who had failed to respond adequately to conventional treatment. Design Cotreatment with GH (4 IU) and human menopausal gonadotropin, 150IU of follicle-stimulating hormone and 150IU of luteinizing hormone (LH), three times a week, and human chorionic gonadotropin, 2,500 IU, two times a week for 24 weeks after unsuccessful treatment for 12 weeks with either pulsatile LH-releasing hormone or gonadotropins. Setting Specialist Reproductive Endocrine Unit. Patients, Participants Seven patients, four of whom had failed to respond adequately to the conventional treatment. Main Outcome Measures Serum testosterone (T), estradiol, and sperm production, testicular and semen volume, and serum insulin-like growth factor-I and inhibin concentrations. Results Of the four patients who received cotreatment with GH, three increased T secretion (>11 nmol/L) within a relatively short period of time, two produced adequate amount of sperm (13 and 12 × 10 6 /mL), and one of them impregnated his wife. One patient did not respond. Conclusion The results offer a new approach to the problem of induction of spermatogenesis in patients who respond poorly to conventional treatment because cotreatment with GH enhanced T secretion and sperm production in a relatively short period of time.

Association of poorly controlled diabetes with low serum leptin in morbid obesity

OBJECTIVES: Leptin may be involved in the regulation of body weight, food intake, and energy expenditure. In view of a possible link between leptin concentrations and diabetes that has been suggested in obese rodents, we investigated the potential relationship between serum leptin concentrations and hyperglycaemia in French patients with morbid obesity. SUBJECTS: Fasting leptin concentrations were measured in 241 morbidly obese patients with various degrees of glucose tolerance in a cross‐sectional study. RESULTS: Fasting serum leptin concentrations did not differ between normoglycaemic (NG, 61.5±24.0 ng/ml) and glucose intolerant morbidly obese subjects (IGT, 56.5±18.5 ng/ml) and were slightly lower in those with controlled diabetes (55.1±30.3 ng/ml, P=0.06 when compared to NG subjects). In contrast, leptin concentrations were 30% lower in patients with poorly controlled diabetes (43.0±22.2 ng/ml, P=0.001 vs NG subjects). Leptin concentrations were negatively correlated with fasting glucose in all groups combined (ρ=−0.24, P=0.0001) and particularly in NIDDM subjects (ρ=0.31, P=0.0054). Although leptin concentrations were higher in women than in men, similar significant correlation with fasting glucose was found when females were analyzed separately. A positive correlation was found with BMI (ρ=0.25, P=0.0001) in all groups. Multivariate analysis revealed that fasting glucose was independently associated with serum leptin concentrations (F=12.5, P=0.0005). Sex, age, BMI, waist/hip ratio, fasting glucose and insulin, total cholesterol and triglycerides, tested in the model, explained 42% of the leptin variability in this population. CONCLUSIONS: Poorly controlled diabetes was accompanied by a significant reduction of serum leptin concentrations in morbidly obese subjects. We suggest that a relative leptin deficiency (lower than expected for the BMI) associated with insulin deficiency in this population might contribute to a vicious cycle maintaining (or even worsening) obesity itself and/or its metabolic complications.

Baseline Inhibin B and Anti-Mullerian Hormone Measurements for Diagnosis of Hypogonadotropic Hypogonadism (HH) in Boys with Delayed Puberty

CONTEXT The diagnosis of isolated hypogonadotropic hypogonadism (IHH) in boys with delayed puberty is challenging, as may be the diagnosis of hypogonadotropic hypogonadism (HH) in boys with combined pituitary hormone deficiency (CPHD). Yet, the therapeutic choices for puberty induction depend on accurate diagnosis and may influence future fertility. OBJECTIVE The aim was to assess the utility of baseline inhibin B (INHB) and anti-Mullerian hormone (AMH) measurements to discriminate HH from constitutional delay of puberty (CDP). Both hormones are produced by Sertoli cells upon FSH stimulation. Moreover, prepubertal AMH levels are high as a reflection of Sertoli cell integrity. PATIENTS We studied 82 boys aged 14 to 18 yr with pubertal delay: 16 had IHH, 15 congenital HH within CPHD, and 51 CDP, as confirmed by follow-up. Subjects were genital stage 1 (testis volume<3 ml; 9 IHH, 7 CPHD, and 23 CDP) or early stage 2 (testis volume, 3-6 ml; 7 IHH, 8 CPHD, and 28 CDP). RESULTS Age and testis volume were similar in the three groups. Compared with CDP subjects, IHH and CPHD subjects had lower INHB, testosterone, FSH, and LH concentrations (P<0.05), whereas AMH concentration was lower only in IHH and CPHD subjects with genital stage 1, likely reflecting a smaller pool of Sertoli cells in profound HH. In IHH and CPHD boys with genital stage 1, sensitivity and specificity were 100% for INHB concentration of 35 pg/ml or less. In IHH and CPHD boys with genital stage 2, sensitivities were 86 and 80%, whereas specificities were 92% and 88%, respectively, for an INHB concentration of 65 pg/ml or less. The performance of testosterone, AMH, FSH, and LH measurements was lower. No combination or ratio of hormones performed better than INHB alone. CONCLUSION Discrimination of HH from CDP with baseline INHB measurement was excellent in subjects with genital stage 1 and fair in subjects with genital stage 2.

Prevalence of binge eating disorder in different populations of French women

OBJECTIVE The aim of this study was to evaluate the prevalence of binge eating disorder (BED) in nonpatient women in the community and in weight control groups in France and to compare the characteristics of weight history of subjects with and without BED. METHODS Eating patterns over the past six months were studied by questionnaires in self-report format. The prevalence of binge eating, BED, and bulimia was studied in 447 nonpatient women and in subjects seeking help for weight control either in private practice (PP, n = 292) or in a hospital department of nutrition (H, n = 85). RESULTS BED was common (PP = 9%; H = 15%) among patients attending weight control clinics but very rare in the community (0.7%). The disorder was associated with a history of weight fluctuations. Many subjects with BED referred to regular use of diet pills (29%) or vomiting (39%) but the prevalence of these strategies of weight control fell short for the requirement for the diagnosis of bulimia. DISCUSSION BED was common in subjects seeking help for weight control and extremely rare in the community nonpatients.