Najiba Lahlou

Publications (28)209.52 Total impact

• Article: Le déficit androgénique lié à l’âge: du diagnostic biologique au traitement substitutif

  Marc Roger, Najiba Lahlou
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  ABSTRACT: Le déficit androgénique lié à l’âge (DALA) suscite un intérêt croissant étant donné l’allongement de la vie dans les pays développés et la possibilité d’un traitement substitutif supposé protéger les hommes âgés contre les effets de la carence en testostérone. Plusieurs études épidémiologiques ont établi que les paramètres hormonaux les mieux corrélés avec la densité minérale osseuse, la masse musculaire et la force musculaire étaient le taux de la testostérone libre ou de la testostérone biodisponible, ainsi que le taux de l’estradiol biodisponible, c’est-à-dire non lié à la testostérone-estradiol binding globulin (TeBG). En effet la diminution avec l’âge de la sécrétion testiculaire est masquée par l’augmentation du taux de la TeBG si l’on se contente de mesurer la testostérone totale. Une autre difficulté pour le diagnostic biologique du DALA est l’incertitude quant aux seuils à prendre en considération. Certes, par consensus tacite, la plupart des investigateurs considèrent que sont déficitaires les hommes dont le taux de testostérone biodisponible est au-dessous de la limite inférieure des hommes adultes jeunes, généralement le cinquième percentile. En réalité, cette attitude empirique n’est pas totalement validée scientifiquement, d’autant que l’on ignore tout de l’évolution avec l’âge de la sensibilité des récepteurs androgéniques. Mais cette prise de position permet d’identifier les hommes âgés candidats à un traitement hormonal substitutif. Actuellement plusieurs formulations de testostérone sont disponibles, permettant son administration par voie orale, intra0musculaire, ou transdermique. L’undécanoate de testostérone (Pantestone®) pris par la bouche est en principe transporté par la voie du canal thoracique, court-circuitant partiellement le métabolisme hépatique. L’énanthate de testostérone (Androtardyl®) et l’heptylate de testostérone (Testostérone Heptylate®) sont des préparations huileuses retards actives 2 ou 3 semaines. Mais les taux obtenus peuvent être supra-physiologiques dans les jours suivant l’injection. Les formulations transdermiques sont d’apparition plus récente. Le dispositif Androderm® est un patch d’application quotidienne, dont la cinétique d’absorption mime le rythme circadien de la testostérone, mais les taux de dihydrotestostérone (DHT) peuvent être supra-physiologiques. La testostérone en gel (Androgel®) produit, par une seule application quotidienne, des taux stables de testostérone, DHT et estradiol. Le choix entre ces différentes formulations dépend des besoins du patient, de ses demandes et de sa compliance pour un mode d’administration donné. There is increasing interest in the assessment of testicular function in aging men, probably because of an increasing number of males above 60 years and because of the emerging gap in the medical management of aging between men and women. In the last three decades, the endocrinological problems of menopause have been thoroughly taken into consideration, while the decline in testis activity in the so called andropause was only recently recognized to deserve a similar interest. In fact, testis endocrine function is not so easy to evaluate in elderly men: total testosterone (tT) level declines very slowly and it is a fallacious index of testis function because of the increase in testosterone/estradiol binding globulin (TeBG) levels in aging males. Free testosterone level is an accurate index when measured by reference techniques, while routine direct assays using testosterone analogues have been proven to be unreliable diagnostic tools. The measurement of bioavailable testosterone (bT) after ammonium sulfate precipitation of TeBG-bound testosterone is currently considered as the method of choice for diagnosing ADAM syndrome. Indeed, in aging males, bT levels are more closely correlated than tT with bone mineral density, muscle strength and muscle mass. Bioavailable estradiol is also a reliable index of testis aging in elderly males and is strongly correlated with bone mineral density. Unfortunately a serious expertise is needed for accurate measurement of bioavailable estradiol levels. Another difficulty in the diagnosis of ADAM syndrome in the uncertainty in the bT threshold to be taken into account. The 5th percentile of bT levels in young adult men can be arbitrarily choosen; however, there is no definite proof that such a threshold is totally appropriate, since no data are available regarding the evolution with years of androgen receptor sensitivity. Nevertheless, identifying androgen deficiency by means of bT measurement may lead to hormone replacement therapy, at least as a therapeutic test. Several formulations of testosterone are currently available using oral, intra-muscular and transdermal routes. Testosterone undecanoate (Pantestone®) is given orally and is supposed to reach the blood stream via the lymph thoracic channel. Intra-muscular testosterone in oil (Androtardyl® and Testosterone Heptylate®) can maintain high testosterone levels for two to three weeks, but can also induce supra-physiological levels of testosterone and dihydrotestosterone (DHT) within the first week after injection. Transdermal formulations have been recently proposed as non-invasive ways to administer testosterone while by-passing liver metabolism. Permeation enhanced transdermal system (Androderm®) can mimic the testosterone circadian rythm, but testosterone levels may be supra-physiological for several hours. DHT levels however are generally maintained whithin physiological values. Testosterone gel (Androgel®) can induce stable and physiological levels of testosterone, DHT and estradiol. Care should be taken to avoid contamination of the familial environment by testosterone after its application. The choice between these formulations depends obviously on the patient’s needs, the patient’s requests, and the patient’s compliance with a particular formulation.
  Andrologie 04/2012; 12(2):138-148.
• Article: Clinical and hormonal status of infants with nonmosaic XXY karyotype.

  Najiba Lahlou, Ilene Fennoy, Judith L Ross, Claire Bouvattier, Marc Roger
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  ABSTRACT: To compare our recent findings in a cohort of 77 nonmosaic XXY infants <2 years of age with clinical and biological features already reported. The majority of reported XXY neonates had normal external genitalia. Only undescended testes and/or micropenis were identified reasons for referral. Delayed ambulation and speech skills were also indications for postnatally karyotyping. All subjects from our cohort (73 prenatally detected subjects, five postnatal diagnoses) had height and weight within the normal range, and were not dysmorphic. Insulin-like-peptide-3 and testosterone secretion by Leydig cells appeared normally sensitive to luteinizing hormone. In reported studies, inhibin B levels were within normal range, anti-Mullerian hormone levels were normal or high and follicle-stimulating hormone (FSH) levels were significantly higher than control values, data consistent with a relative resistance to FSH. Early detection of Klinefelter syndrome is desirable for prospectively monitoring the apparition of developmental problems and the progressive decline in the tubular function of the testis, with the hope of designing future conservative interventions before germ cell degeneration is completed.
  Acta Paediatrica 03/2011; 100(6):824-9. · 2.07 Impact Factor
• Article: Assessment of Leydig and Sertoli cell functions in infants with nonmosaic Klinefelter syndrome: insulin-like peptide 3 levels are normal and positively correlated with LH levels.

  Sylvie Cabrol, Judith L Ross, Ilene Fennoy, Claire Bouvattier, Marc Roger, Najiba Lahlou
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  ABSTRACT: Klinefelter syndrome (KS) is the most common sex chromosome disorder and a major cause of male infertility. In adult patients, serum inhibin B and anti-Mullerian-hormone (AMH) are undetectable, testosterone secretion is often impaired, and the tubules are depleted of germ cells. Before puberty, inhibin B, AMH, and testosterone levels are within the normal range. Sertoli and Leydig cell secretions, including insulin-like peptide-3 (INSL3), were evaluated in infants with nonmosaic XXY karyotype to assess testicular function soon after birth. The study was conducted in four University Pediatric Departments from the United States and France. Sixty-eight prenatally diagnosed infants aged 2-750 d were enrolled. Serum FSH, LH, inhibin B, AMH, and INSL3 were measured by immunoassay, and testosterone was measured by tandem mass-spectrometry. In infants with KS, INSL3 levels transiently increased at 2-3 months of age and were significantly correlated with testosterone (Spearman r = 0.57) and LH (Spearman r = 0.73) levels. They did not differ from controls. Testosterone levels were within the normal range, but most of them were below the median of controls. Inhibin B and AMH levels were also within normal range. Inhibin B was correlated with FSH (Spearman r = 0.49). AMH was not correlated with FSH or testosterone. FSH levels were above normal in 25% of patients, despite normal inhibin B levels. In infants with KS, Leydig cells are normally sensitive to the LH proliferative effect. In contrast, the Sertoli cell sensitivity to FSH is questionable, which may be prophetic of the postpubertal Sertoli cell resistance to FSH.
  The Journal of clinical endocrinology and metabolism 02/2011; 96(4):E746-53. · 6.50 Impact Factor
• Article: Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty.

  Régis Coutant, Estelle Biette-Demeneix, Claire Bouvattier, Natacha Bouhours-Nouet, Frédérique Gatelais, Sylvie Dufresne, Stéphanie Rouleau, Najiba Lahlou
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  ABSTRACT: 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. 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. 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). 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. 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.
  The Journal of clinical endocrinology and metabolism 12/2010; 95(12):5225-32. · 6.50 Impact Factor
• Article: Near normalization of adult height and body proportions by growth hormone in pycnodysostosis.

  Anya Rothenbühler, Catherine Piquard, Iva Gueorguieva, Najiba Lahlou, Agnès Linglart, Pierre Bougnères
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  ABSTRACT: Mutations in the cathepsin K gene (CTSK) cause a very rare form of short-limb dwarfism called pyknodysostosis (online inheritance in man 265800) that reduces adult height to 130-150 cm. To study the effects of GH in children with pyknodysostosis. This was a pilot open study of three children with pyknodysostosis (P1, P2, P3) and 16 age-matched children with idiopathic short stature (ISS) treated with a similar IGF-I-based dosing of GH therapy. P1, P2, and P3 received a mean GH dose of 29, 67, and 120 microg/kg x d, respectively, during 12, 6.5, and 5 yr, whereas the ISS group received a mean dose of 62 +/- 21 microg/kg x d during 5.4 +/- 2 yr. P1, P2, and P3 had the typical clinical and radiological features of pyknodysostosis. They were shown to carry three different homozygous missense mutations of the CTSK gene. After onset of GH at 4.5, 5.4, and 10.9 yr of age, respectively, height increased from -2, -4.2, and -3 SD score to -1, -0.5, and -1 SD score after a 12, 6.5, and 5 yr GH treatment. Remarkably, body disproportion was largely corrected by GH treatment. IGF-I levels in P1, P2, and P3 were within the range of the ISS group. Pyknodysostotic patients can reach near-normal stature and skeletal proportions with a personalized GH treatment targeted at appropriate IGF-I levels. Given the severity of this rare dwarfism, we propose that GH should be offered to affected children.
  The Journal of clinical endocrinology and metabolism 03/2010; 95(6):2827-31. · 6.50 Impact Factor
• Source

  Available from: Emmanuel Payen

  Article: Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.

  Nathalie Cartier, Salima Hacein-Bey-Abina, Cynthia C Bartholomae, Gabor Veres, Manfred Schmidt, Ina Kutschera, Michel Vidaud, Ulrich Abel, Liliane Dal-Cortivo, Laure Caccavelli, [......], Stéphane Blanche, Muriel Audit, Emmanuel Payen, Philippe Leboulch, Bruno l'Homme, Pierre Bougnères, Christof Von Kalle, Alain Fischer, Marina Cavazzana-Calvo, Patrick Aubourg
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  ABSTRACT: X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34+ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.
  Science 11/2009; 326(5954):818-23. · 31.20 Impact Factor
• Source

  Available from: Jan M Wit

  Article: Consensus statement on the use of gonadotropin-releasing hormone analogs in children.

  Jean-Claude Carel, Erica A Eugster, Alan Rogol, Lucia Ghizzoni, Mark R Palmert, Franco Antoniazzi, Sheri Berenbaum, Jean-Pierre Bourguignon, George P Chrousos, Joël Coste, [......], Peter Lee, Deborah P Merke, E Kirk Neely, Wilma Oostdijk, Moshe Phillip, Robert L Rosenfield, Dorothy Shulman, Dennis Styne, Maïthé Tauber, Jan M Wit
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  ABSTRACT: Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents. When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise. Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion. Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement. The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely.
  PEDIATRICS 05/2009; 123(4):e752-62. · 4.47 Impact Factor
• Article: Vitamin D receptor genotype in hypophosphatemic rickets as a predictor of growth and response to treatment.

  Frédéric Jehan, Céline Gaucher, Thi Minh Nguyen, Odile Walrant-Debray, Najiba Lahlou, Christiane Sinding, Michèle Déchaux, Michèle Garabédian
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  ABSTRACT: Treatment of X-linked hypophosphatemic rickets improves bone mineralization and bone deformities, but its effect on skeletal growth is highly variable. Genetic variants in the promoter region of the vitamin D receptor (VDR) gene may explain the response to treatment because this receptor mediates vitamin D action. We studied the VDR promoter haplotype structure in a large cohort of 91 patients with hypophosphatemic rickets including 62 patients receiving 1alpha-hydroxyvitamin D3 derivatives and phosphates from early childhood on. Treatment improved bone deformities and final height, but 39% of treated patients still had short stature at the end of growth (-2 sd score or below). Height was closely associated with VDR promoter Hap1 genotype. Hap1(-) patients (35% of the cohort) had severe growth defects. This disadvantageous association of Hap1(-) status with height was visible before treatment, under treatment, and on to adulthood. Gender and age at initiation of treatment could not account for the Hap1 effect. No association with growth was found with a polymorphism of the PTH receptor gene otherwise found to be associated with adult height. Compared with Hap1(+) patients, those who were Hap1(-) had a higher urinary calcium response to 1alpha-hydroxyvitamin D3 and had significantly lower circulating FGF23 levels (C-terminal assay), taking into account their phosphate and 1alpha-hydroxyvitamin D3 intakes. The present work identifies the VDR promoter genotype as a key predictor of growth under treatment with 1alpha-hydroxyvitamin D3 derivatives in patients with hypophosphatemic rickets, including those with established PHEX alterations. The VDR promoter genotype appears to provide valuable information for adjusting treatment and for deciding upon the utility of early GH therapy.
  Journal of Clinical Endocrinology &amp Metabolism 10/2008; 93(12):4672-82. · 6.50 Impact Factor
• Article: Gonadotrophic status in adolescents with pituitary stalk interruption syndrome.

  Diane Rottembourg, Agnès Linglart, Catherine Adamsbaum, Najiba Lahlou, Cécile Teinturier, Pierre Bougnères, Jean-Claude Carel
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  ABSTRACT: Pituitary stalk interruption syndrome (PSIS) is a frequent cause of GH deficiency (GHD) and is commonly associated with other PH deficiencies (PHDs). Although previous reports have correlated multiple PHDs with severe anatomical lesions, the status of the gonadotrophic axis has not yet been thoroughly analysed. We retrospectively reviewed the medical records of 27 patients (15 males, 12 females) with GHD and PSIS defined by MRI findings. The status of the gonadotrophic axis was evaluated in children who were at least 14.5 years (boys) or 13 years (girls). Out of 27 patients, five displayed spontaneous full pubertal development with normal hormonal values at the final evaluation, whereas 22 of 27 patients (81%) had complete (n = 18) or partial pubertal deficiency. Three girls had primary amenorrhoea with normal gonadotrophin values, raising the possibility of subtle disturbances of gonadotrophin pulsatility. Of the 21 patients with TSH or ACTH deficiency, 17 (81%) had complete gonadotrophin deficiency. Two of our six patients with apparently isolated GHD during childhood had gonadotrophin deficiency. Cryptorchidism was present at birth in six boys (40%). Of these six boys, one had normal pubertal development. Ten of 11 boys with micropenis at birth had gonadotrophin deficiency. Gonadotrophin deficiency is a common finding in adolescents with PSIS and is frequently associated with other PHDs. However its severity is variable, ranging from complete gonadotrophin deficiency to normogonadotrophic amenorrhoea. The occurrence of gonadotrophin deficiency in 33% of children with apparently isolated GHD and PSIS has important implications for the counselling and follow-up of these patients.
  Clinical Endocrinology 08/2008; 69(1):105-11. · 3.17 Impact Factor
• Article: Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome.

  Martha P D Zeger, Andrew R Zinn, Najiba Lahlou, Purita Ramos, Karen Kowal, Carole Samango-Sprouse, Judith L Ross
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  ABSTRACT: To describe the Klinefelter Syndrome (KS) phenotype during childhood in a large cohort. 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. 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. 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.
  The Journal of pediatrics 06/2008; 152(5):716-22. · 4.02 Impact Factor
• Article: Akt phosphorylation in lymphocytes provides an index of in vitro insulin-like growth factor I sensitivity associated with growth hormone-induced growth.

  Chantal Lotton, Danielle Rodrigue, Caroline Elie, Anya Rothenbühler, Najiba Lahlou, Catherine Le Stunff, Pierre Bougnères
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  ABSTRACT: Because IGF-I is the main mediator of GH action on osteogenic cells, individual differences in IGF-I sensitivity are expected to contribute to the variations of GH effects on growth. In GH-treated children, the variable responses in growth rates at a specific IGF-I target level indicate heterogeneity of responses to serum IGF-I exposures. This study tested a cell-based assay as an index of individual IGF-I sensitivity that could help dissect GH pharmacogenetics. Akt phosphorylation (P-Akt) was quantified in response to IGF-I in fresh lymphocytes from 50 short children (25 with idiopathic short stature and 25 born short for gestational age) whose growth parameters were being prospectively monitored during the first year of GH therapy (86 +/- 20 mug/kg.d). Intra-individual triplicate measurements of IGF-I-stimulated P-Akt were reasonably consistent (0.11 < or = sd; mean < or = 0.23). Among the 50 children, the distribution of P-Akt in lymphocytes stimulated by 125 ng/ml IGF-I was closely associated with the growth response to GH administration (univariate P = 0.001). Both GH dosage (P = 0.006) and the fold increase in IGF-I levels (P = 0.04) in response to GH (P = 0.04) were also correlated with the growth response. Lymphocytes are the only IGF-I target cells that can be easily studied in clinical research. IGF-I-stimulated P-Akt in these cells was found to be a predictor of GH efficacy, supporting a significant role of the first steps of IGF-I signaling in the individual variability of GH effects on growth.
  Journal of Clinical Endocrinology &amp Metabolism 04/2008; 93(4):1458-63. · 6.50 Impact Factor
• Article: Impact level of dihydrotestosterone on the hypothalamic-pituitary-leydig cell axis in men.

  Anne Cailleux-Bounacer, Vincent Rohmer, Najiba Lahlou, Hervé Lefebvre, Marc Roger, Jean Marc Kuhn
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  ABSTRACT: Dihydrotestosterone (DHT) the physiologically most potent androgen cannot be aromatised into oestrogen. DHT is used as a treatment for idiopathic gynaecomastia. In order to investigate the different sites of action of DHT on the hypothalamic-pituitary-testicular axis, two groups of adult men were studied. Group I included 10 gonadotropin-releasing hormone (GnRH)-deficient men who were evaluated before and during a pulsatile infusion of GnRH alone for 2 weeks and then in association with DHT given transdermally at doses used in the treatment of gynaecomastia for further two weeks. Luteinizing hormone (LH) pulsatility was assessed at the end of each step of the study. Plasma LH levels were measured every 15 min. Plasma testosterone (T), DHT, oestradiol (E2), free alpha-subunit (FAS) of glycoproteic hormones and LH bioactivity were measured on pooled plasma samples. Group II included 12 healthy men in whom plasma T, DHT and E2 were measured before and then 24, 48 and 72 h after the injection of 5000 IU hCG alone or in combination with either DHT or the pure anti-androgen nilutamide. Two weeks separated each of the 3 hCG testing. In group I, except for bioactive/immunoreactive (B/I) LH ratio which was unchanged, GnRH treatment induced significant rises (p < 0.01) in all plasma hormone levels, LH pulse amplitude and frequency. During treatment with GnRH+DHT, plasma DHT levels increased up to 16.8 +/- 2.5 nm, while plasma hormone levels, B/I LH ratio, LH pulse amplitude and frequency were similar to those obtained with GnRH alone. In group II, the peak of hCG-induced T rise was not modified by either DHT or nilutamide. In contrast, DHT reduced by 50% (p < 0.01) the E2 peak in response to hCG. These data show that DHT exerts no direct action on the pituitary to retroregulate LH secretion and to modify either B/I LH ratio or FAS secretion. Its reducing effect on LH secretion is likely mediated at the hypothalamic level. DHT does not appear to have a physiological influence on Leydig cells steroidogenesis. Administered at therapeutic doses, DHT directly reduces testicular aromatase activity that combined with its antigonadotropic effect leads to the gain in the symptomatic treatment of gynaecomastia.
  International Journal of Andrology 10/2007; 32(1):57-65. · 3.59 Impact Factor
• Article: Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome.

  Régis Coutant, Delphine Mallet, Najiba Lahlou, Natacha Bouhours-Nouet, Agnès Guichet, Lionel Coupris, Anne Croué, Yves Morel
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  ABSTRACT: The clinical and biological features of Sertoli cell and Leydig cell dysfunction are usually investigated when characterizing disorders of sex development in 46,XY individuals: This allows gonadal dysgenesis, a defective development of the gonad, to be distinguished from defects restricted to androgen synthesis or sensitivity. In humans, mutations in steroidogenic factor-1 (SF-1), one of the critical factors involved in testis development, have been reported to cause gonadal dysgenesis with or without adrenal failure in 46,XY individuals. We report a SF-1 mutation that caused ambiguous genitalia associated with strikingly different hormonal phenotypes in two affected 46,XY children from the same family. Hormonal evaluation included testosterone (T), anti-Mullerian hormone (AMH), inhibin B, FSH, and LH measurements during the first weeks of life, a period when physiological activation of the gonadotropin-gonadal system occurs. Direct DNA sequencing of the coding sequence of the SF-1 and the androgen receptor (AR) genes was performed. Both 46,XY children had ambiguous genitalia with no Mullerian structures and no adrenal insufficiency. The older child showed normal elevation of T (up to 7.6 nmol/liter, 2.2 ng/ml), AMH (504 pmol/liter, 70.6 ng/ml), inhibin B (245 pg/ml), FSH, and LH during the first weeks, which led to a presumptive diagnosis of partial androgen insensitivity syndrome. The AR sequence was, however, normal. In the second child, T, AMH, and inhibin B were low, suggesting gonadal dysgenesis. In both children and their mother, a c.536delC frameshift mutation in the SF-1 gene was found. This mutation terminates translation at position 295, removing the ligand-binding domain and the activation function 2 (AF-2) domain, a critical domain for SF-1 transactivating activity. The usual markers of testis dysgenesis may be normal in 46,XY individuals with SF-1 mutation. Screening for SF-1 mutation should be performed in subjects with apparent partial androgen insensitivity syndrome and no mutation in the AR gene.
  Journal of Clinical Endocrinology &amp Metabolism 09/2007; 92(8):2868-73. · 6.50 Impact Factor
• Article: Unexpected mosaicism of R201H-GNAS1 mutant-bearing cells in the testes underlie macro-orchidism without sexual precocity in McCune-Albright syndrome.

  Rodolfo A Rey, Marcela Venara, Régis Coutant, Jean-Baptiste Trabut, Stéphanie Rouleau, Najiba Lahlou, Charles Sultan, Jean-Marie Limal, Jean-Yves Picard, Serge Lumbroso
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  ABSTRACT: McCune-Albright syndrome (MAS), usually presenting with polyostotic bone dysplasia, café-au-lait skin lesions and sexual precocity, results from a somatic activating mutation of the GNAS1 gene, which encodes the Gs-alpha protein involved in signalling of several G-protein-coupled receptors. The clinical spectrum depends on tissue distribution of mutant-bearing cells. Sexual precocity has been ascribed to the occurrence of a mutant GNAS1 allele in the gonadal anlage, from which all somatic cells of the differentiated gonads arise. In boys, precocious activation of Leydig cell androgen secretion results in pubertal spermatogenesis, leading to testicular enlargement, and in the development of secondary sex characteristics. However, sexual precocity is rare in MAS males while isolated testicular enlargement is frequently observed. We recently reported the case of a boy with macro-orchidism and signs of Sertoli cell hyperactivity but no signs of hyperandrogenism, which was unexpected since Gs-alpha is functional in both Sertoli and Leydig cells. To understand its pathophysiology, we microdissected an available testicular biopsy to separate Sertoli from Leydig cells. The R201H-GNAS1 allele was present only in Sertoli cells, resulting in isolated Sertoli cell hyperfunction, evidenced by increased AMH expression and cell hyperplasia leading to prepubertal macro-orchidism, with no signs of Leydig cell activation. The different early embryologic origin of precursors contributing to Sertoli and Leydig cell lineages may underlie the differential existence of the mutated GNAS1 gene. Lack of occurrence of the mutation in Leydig cells may explain why sexual precocity is rarely observed in boys with MAS.
  Human Molecular Genetics 01/2007; 15(24):3538-43. · 7.64 Impact Factor
• Article: Activating mutations in the luteinizing hormone receptor gene: a human model of non-follicle-stimulating hormone-dependent inhibin production and germ cell maturation.

  Leandro Soriano-Guillen, Valerie Mitchell, Jean-Claude Carel, Patrick Barbet, Marc Roger, Najiba Lahlou
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  ABSTRACT: Familial male-limited precocious puberty is a dominant autosomal genetic disease caused by activating LH receptor gene mutations, clinically expressed only in males. In preliminary studies, in addition to the expected testosterone increase, we found high inhibin B levels before the age of normal puberty. The objective of the study was to assess the cellular origin of serum inhibin thanks to testis section immunostaining. Serum testosterone, gonadotropin, inhibin B, pan-alphaC-inhibin, and anti-Mullerian hormone levels were measured. Immunostaining was performed using specific anti-alpha- and anti-beta-subunit antibodies. Five boys from three families (mutation M398T or I542L) were investigated at onset (2-6 yr), on ketoconazole treatment, and at adolescence. Testis biopsies were performed in three subjects before the disease was fully characterized. The high testosterone levels were suppressed by ketoconazole. Anti-Mullerian hormone levels were inversely related to testosterone: low at diagnosis, elevated after testosterone suppression. Despite FSH suppression, inhibin B and pan-alphaC-inhibin levels were high from clinical onset to adolescence. Biopsy specimens showed normal Sertoli cell complement and germ cell maturation until the spermatocyte II stage. Sertoli and Leydig cells displayed positive inhibin alpha-subunit immunostaining. Only Leydig cells and spermatogonia stained positively for the inhibin betaB-subunit. Familial male-limited precocious puberty is a unique model of inhibin B secretion, demonstrating that Leydig cells can produce significant amounts of the dimeric molecule. Our results also suggest that the pubertal FSH rise is not required for full expression of the two inhibin B genes and for the initiation of germ cell maturation.
  Journal of Clinical Endocrinology &amp Metabolism 09/2006; 91(8):3041-7. · 6.50 Impact Factor
• Article: Prepubertal gynecomastia in Peutz-Jeghers syndrome: incomplete penetrance in a familial case and management with an aromatase inhibitor.

  Hervé Lefevre, Claire Bouvattier, Najiba Lahlou, Catherine Adamsbaum, Pierre Bougnères, Jean-Claude Carel
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  ABSTRACT: Peutz-Jeghers syndrome (PJS) is a rare autosomal-dominant disorder characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation and increased predisposition to various neoplasms. Endocrine manifestations in PJS include gynecomastia due to calcified Sertoli cell testicular tumors usually referred to as large-cell calcifying Sertoli cell tumors (LSCT). To evaluate the value of endocrine markers and aromatase inhibitor treatment in children with PJS and LSCT. Familial cases, followed in a tertiary care center. Two male siblings aged 7 and 9 years with PJS and LSCT. Third generation aromatase inhibitor (anastrozole) in one of the patients. Longitudinal measurements of sex-steroids, gonadotropins, Sertoli cell markers and auxological evaluation. The two male siblings with PJS had similar bilateral multifocal testicular calcifications and biochemical evidence of Sertoli cell dysfunction manifested by elevated plasma inhibin-alpha levels. Only one sibling had gynecomastia. Estradiol levels were normal in both. During treatment with anastrozole, estradiol levels, growth and skeletal maturation, as well as Sertoli cell markers (inhibin B, inhibin-alpha and anti-Mullerian hormone) decreased. Inhibin-alpha may be considered as a marker for LSCT in children with PJS, pointing to a specific defect in inhibin regulation in this condition. Moreover, the decrease in Sertoli cell markers during aromatase inhibitor treatment suggests that increased estrogen production is a primary event regulating downstream production of Sertoli cell peptides. Anastrozole is efficient in controlling the clinical features of the disease and should be proposed as an alternative to bilateral orchidectomy, which is often performed in this condition.
  European Journal of Endocrinology 03/2006; 154(2):221-7. · 3.42 Impact Factor
• Article: Three-month sustained-release triptorelin (11.25 mg) in the treatment of central precocious puberty.

  Jean-Claude Carel, Joëlle Blumberg, Christine Seymour, Catherine Adamsbaum, Najiba Lahlou
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  ABSTRACT: Depot GnRH agonists are commonly used in the treatment of central precocious puberty (CPP). The triptorelin 11.25 mg 3-month depot, currently used in adult indications, had not previously been evaluated in CPP. This was a multicenter, open-label, 12 month trial conducted in 64 CPP children (54 girls and 10 boys), treated quarterly. Children with a clinical onset of pubertal development before the age of 8 years (girls) or 9 years (boys), pubertal response of LH to GnRH > or = 7 IU/l, advanced bone age > 1 year, enlarged uterus (> or = 36 mm) and testosterone level > or = 0.5 ng/ml (boys), were included. Suppression of gonadotropic activation, as determined from serum LH, FSH, estradiol or testosterone, and pubertal signs were assessed at Months 3, 6 and 12. GnRH-stimulated peak LH < or = 3 IU/l, the main efficacy criterion, was met in 53 out of 62 (85%), 60 out of 62 (97%) and 56 out of 59 (95%) of the children at Months 3, 6 and 12 respectively. Serum FSH and sex steroids were also significantly reduced, while pubertal development regressed in most patients. Mean residual triptorelin levels were stable from Month 3 through to Month 12. The triptorelin 3-month depot was well tolerated. Severe injection pain was experienced in only one instance. Five girls experienced mild-to-moderate or severe (one girl) withdrawal bleeding. The triptorelin 3-month depot efficiently suppresses the pituitary-gonadal axis and pubertal development in children with CPP. This formulation allows a 3-fold reduction, over the once-a-month depot, in the number of i.m. injections required each year.
  European Journal of Endocrinology 01/2006; 154(1):119-24. · 3.42 Impact Factor
• Article: [Andrew Schally, discover of GnRH].

  Philippe Bouchard, Jean-Louis Chaussain, Louis Deheunin, Najiba Lahlou, Marc Roger
  La Revue du praticien 02/2005; Spec. No:3.
• Article: Adult height after ketoconazole treatment in patients with familial male-limited precocious puberty.

  Leandro Soriano-Guillén, Najiba Lahlou, Geneviève Chauvet, Marc Roger, Jean Louis Chaussain, Jean Claude Carel
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  ABSTRACT: Familial male-limited precocious puberty is a rare cause of precocious puberty due to activating mutations of the LH receptor, leading to early onset virilization and short stature. Two therapeutic approaches have been proposed: the P450 cytochrome inhibitor ketoconazole or combined treatment with spironolactone and testolactone. Results on adult heights have not been reported to date after these two treatments, and in this study we present results from five patients treated with ketoconazole at a median dose of 16.2 mg/kg.d for a median of 6.2 yr. Adult height was 173 cm (median; interquartile range, 14), similar to target height (175 cm; interquartile range, 9) and significantly higher than pretreatment predicted height (165 cm; interquartile range, 12; P < 0.01). During treatment, 39 of 58 (68%) testosterone measurements were less than 0.5 ng/ml (1.7 nmol/liter), nine of 58 (15%) were between 0.5 and 1 ng/ml (3.5 nmol/liter), and 10 of 58 (17%) were above 1 ng/ml. We observed a physiological increase in GnRH-stimulated LH levels after the age of 10 yr, and none of the patients had early activation of the gonadotropic axis. Liver tolerance was excellent, and only one patient had a transient and modest increase in serum transaminases. We conclude that ketoconazole is an efficient and well tolerated long-term treatment of familial male-limited precocious puberty that should be proposed as a first line therapy.
  Journal of Clinical Endocrinology &amp Metabolism 01/2005; 90(1):147-51. · 6.50 Impact Factor
• Article: Early androgen deficiency in infants and young boys with 47,XXY Klinefelter syndrome.

  Judith L Ross, Carole Samango-Sprouse, Najiba Lahlou, Karen Kowal, Frederick F Elder, Andrew Zinn
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  ABSTRACT: 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. 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. 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 < or =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. 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.
  Hormone Research 01/2005; 64(1):39-45. · 2.48 Impact Factor