GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty.

STUDY QUESTION: Are GnRH tests and serum inhibin B levels sufficiently discriminating to distinguish transient constitutional delay of growth and puberty (CDGP) from congenital hypogonadotropic hypogonadism (CHH) that affects reproductive health for life? SUMMARY ANSWER: Both parameters lack the specificity to discriminate CDGP from CHH. WHAT IS KNOWN ALREADY: GnRH tests and inhibin B levels have been proposed to differentiate CDGP from CHH. However, their diagnostic accuracies have been hampered by the small numbers of CHH included and enrichment of CHH patients with more severe forms. STUDY DESIGN, SIZE, DURATION: The aim of this study was to assess the diagnostic performance of GnRH tests and inhibin B measurements in a large cohort of CHH male patients with the whole reproductive spectrum. From 2008 to 2018, 232 males were assessed: 127 with CHH, 74 with CDGP and 31 healthy controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were enrolled in two French academic referral centres. The following measurements were taken: testicular volume (TV), serum testosterone, inhibin B, LH and FSH, both at baseline and following the GnRH test. MAIN RESULTS AND THE ROLE OF CHANCE: Among CHH patients, the LH response to the GnRH test was very variable and correlated with TV. Among CDGP patients, the LH peak was also variable and 47% of CHH patients had peak LH levels overlapping with the CDGP group. However, no patients with CDGP had an LH peak below 4.0 IU/l, while 53% CHH patients had LH peak below this threshold. Among CHH patients, inhibin B levels were also variable and correlated with TV and peak LH. Inhibin B was significantly lower in CHH patients than in CDGP patients but 50% of CHH values overlapped with CDGP values. Interestingly, all patients with CDGP had inhibin B levels above 35 pg/ml but 50% of CHH patients also had levels above this threshold. LIMITATIONS, REASONS FOR CAUTION: As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here. WIDER IMPLICATIONS OF THE FINDINGS: Peak LH and basal inhibin B levels are variable in both CHH and CDGP with significant overlap. Both parameters lack specificity and sensitivity to efficiently discriminate CHH from CDGP. This reflects the varying degree of gonadotropin deficiency inherent to CHH. These two diagnostic procedures may misdiagnose partial forms of isolated (non-syndromic) CHH, allowing them to be erroneously considered as CDGP. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Agence Française de Lutte contre le Dopage: Grant Hypoproteo AFLD-10 (to J.Y.); Agence Nationale de la Recherche (ANR): Grant ANR-09-GENO-017-01 (to J.Y.); European Cooperation in Science and Technology, COST Action BM1105; Programme Hospitalier de Recherche Clinique (PHRC), French Ministry of Health: PHRC-2009 HYPO-PROTEO (to J.Y.); and Programme Hospitalier de Recherche Clinique (PHRC) "Variété", French Ministry of Health, N° P081216/IDRCB 2009-A00892-55 (to P.C.). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Prevalence of KISS1 Receptor mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study.

STUDY QUESTION: What is the exact prevalence of Kisspeptin Receptor (KISS1R) mutations in the population of patients with normosmic congenital hypogonadotrophic hypogonadism (nCHH) by comparison with other genes, involved in gonadotrophin-releasing hormone (GnRH) release or action? SUMMARY ANSWER: KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases and were less prevalent than GnRH Receptor (GNRHR) mutations. WHAT IS KNOWN ALREADY: The respective prevalence of each of the genetic causes of nCHH is unclear. Large series of patients are very rare and suffer from heterogeneity of the population of CHH studied. STUDY DESIGN, SIZE, DURATION: Patients with nCHH were consecutively enrolled in a single French referral centre and were gradually tested for KISS1R between January 2006 and April 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 603 patients with nCHH (399 men and 204 women) were diagnosed at the Bicêtre Hospital and underwent KISS1R analysis. The GNRHR, tachykinin receptor 3 (TACR3), gonadotrophin-releasing hormone 1 (GNRH1), tachykinin 3 (TAC3) and KISS1 genes were also sequenced. Functional characterization of KISS1R mutations included a study of signal transduction using a reporter gene (serum response element-luciferase (SRE-Luc) involved in the mitogen-activated protein (MAP) kinase pathway. MAIN RESULTS AND THE ROLE OF CHANCE: We detected 15 KISS1R variants (10 novel), in 12 of the 603 patients (2.0%, 95% CI [0.9-3.1]. KISS1R mutations were less prevalent than GNRHR (4.7%) and TACR3 (2.6%) mutations but more prevalent than GNRH1 (1.5%), TAC3 (1.0%) and KISS1 (0%) mutations. KISS1R mutants were present in the biallelic state in 8 of the 12 patients concerned. Among 5 men with biallelic KISS1R mutations, 4 had either micropenis or cryptorchidism. In vitro analysis of the 5 new variants present in the biallelic state (C95W, Y103*, C115W, P176R and A287E) showed a loss of function. LIMITATIONS, REASONS FOR CAUTION: The prevalence of TACR3, GNRH1, TAC3 and KISS1 mutations was calculated from a smaller number of nCHH patients than KISS1R and GNRHR. This should prompt caution concerning the reported prevalence of mutations in these four genes. WIDER IMPLICATIONS OF THE FINDINGS: We show that KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases. Together, the genes analysed here were mutated in fewer than 15% of patients, suggesting a role of other genes in nCHH. The presence of cryptorchidism and/or micropenis in the majority of men with biallelic KISS1R mutations strongly suggests that this gene is essential for prenatal GnRH secretion. STUDY FUNDING, COMPETING INTERESTS: This work was supported in part by grants from Paris-Sud University (Bonus Qualité Recherche, and Attractivité grants) to J.B., French Ministry of Health, Hospital Clinical Research Program on Rare Diseases. Assistance Publique Hôpitaux de Paris, Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO) to J.Y. C.P. was supported by student fellowships 'Année Recherche' from Agence Régionale de Santé Provence Alpes Côtes d'Azur. The authors have nothing to disclose.

Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life.

Kallmann syndrome (KS) patients carrying FGFR1 mutations can transmit the disorder to their offspring as can asymptomatic female carriers of mutations in KAL1. We describe for the first time two cases in which KS was suspected during fetal life because of the family context and malformation detection by fetal ultrasound: syndactyly or unilateral renal agenesis in subjects with respectively FGFR1 and KAL1 mutations. In relevant family history, ultrasound monitoring can detect KS associated signs before birth and thus enable neonatal diagnosis and early management. These observations also underline the importance of genetic counselling for patients who may transmit KS to their offspring.

Terapia hormonal en persona transgénero según world professional association for transgender health (WPATH) () y guías clinicas de la endocrine society. () / Hormone therapy in transgender person according to world professional association for transgender health (WPATH) and clinical guidelines of the endocrine society

RESUMEN La identidad de género es la percepción intrínseca de una persona de ser hombre, mujer o alguna alternativa de género. Las personas transgénero perciben estar en un cuerpo equivocado, ya que se sienten del sexo opuesto al biológico. Cuando esta incongruencia entre identidad de género y el fenotipo físico del sexo asignado, genera gran angustia, ansiedad y malestar persistente, se denomina disforia de género. Se estima que el 0,4%- 1.3% de la población mundial experimentan distintos grados de Disforia de Género. (3), no todas las personas con disforia de género tienen las mismas necesidades, por lo que la evaluación del objetivo personal para lograr bienestar es muy importante. Todas las intervenciones médicas conllevan riesgos, por lo que, la comprensión de éstos últimos, la adherencia y el manejo por profesionales capacitados los minimiza. En Revista de la Sociedad Chilena de Obstetricia y Ginecología Infantil y de la Adolescencia, recientemente hemos publicado dos artículos de revisión sobre la introducción a la Hormonoterapia en personas transgénero, objetivos de la terapia, transición en la adolescencia, y la transición masculino a femenino, por lo que éste escrito se concentrará sólo en los Riesgos de la Terapia Hormonal en la transición. (4,5)

SUMMARY Gender identity is the intrinsic perception of a person to be a man, woman or some gender alternative. Transgender people feel that they are in the wrong body, since they feel the opposite sex to the assigned. When this incongruence between gender identity and the physical phenotype generates great anguish, anxiety and persistent discomfort, it is called gender dysphoria. It is estimated that 0.4% −1.3% of the world population experience different degrees of Gender Dysphoria. (3), and not all people with gender dysphoria have the same needs, so the evaluation of the personal goal to achieve well-being is very important. All medical interventions involve risks, so the understanding of the latter, adherence and management by trained professionals minimizes them. In the Journal of the Chilean Society of Obstetrics and Child and Adolescent Gynecology, we have recently published two review articles on the introduction to Hormonotherapy in transgender people, objectives of therapy, transition in adolescence, and the male to female transition, so this writing will focus only on the Risks of Hormonal Therapy in the transition. (4,5)

Terapia hormonal en la transición femenino a masculino (ftm), androgénica, para trans masculino o para hombre transgénero / Hormone Therapy in Female to Male Transition (FTM), Androgenic, Trans Male, or Transgender Male

RESUMEN La transexualidad, o el ser transgénero según la nomenclatura actual, describe a personas que persistentemente buscan ser aceptados como miembros del sexo opuesto, desean cambiar sus caracteres sexuales primarios y/o secundarios a través de intervenciones médicas tanto hormonales como quirúrgicas para feminizarse o masculinizarse. (Tabla 1) Esta discordancia entre su "sexo biológico" y "psicológico" genera estrés clínicamente significativo con rechazo profundo al cuerpo del sexo anatómico, al género asignado al nacer y, por ende, alteración persistente en el funcionamiento diario (mayor a 6 meses), se denomina disforia de género, sienten que nacieron en el "cuerpo equivocado". El objetivo de la intervención médica es mejorar la disforia de género y, por consiguiente, mejora el bienestar y la calidad de vida de las personas trans. En Revista de la Sociedad Chilena de Obstetricia y Ginecología Infantil y de la Adolescencia, recientemente hemos publicado dos artículos de revisión sobre la introducción a la Hormonoterapia en personas transexuales, objetivos de la terapia, transición en la adolescencia, y la transición masculino a femenino, por lo que éste escrito se concentrará sólo en la Terapia Hormonal de la transición femenino a Masculino (FTM), son personas que transitan de Mujer a Hombre, o transgénero masculino o trans masculino. (1,2)

ABSTRACT Transsexuality, or being transgender according to the current nomenclature, describes people who persistently seek to be accepted as members of the opposite sex, wish to change their primary and / or secondary sexual characteristics through both hormonal and surgical medical interventions to feminize or masculinize themselves. (Table 1) This discordance between their "biological" and "psychological" sex, generates clinically significant stress with profound rejection of the body of the anatomical sex, the gender assigned at birth and, therefore, persistent alteration in daily functioning (more than 6 months), is called gender dysphoria feel that they were born in the "wrong Body". The goal of medical intervention is to improve gender dysphoria and, consequently, improve the well-being and quality of life of transgender people. In the Journal of the Chilean Society of Obstetrics and Child and Adolescent Gynecology, we have recently published two review articles on the introduction of Hormonotherapy in transgender people, goals of therapy, transition in adolescence, and the male-to-female transition, so this paper will focus only on Hormonal Therapy of the female to male transition (FTM), are people who transit from woman to man, or male trans, male transgender. (1,2)