Development of CHH family recombinant hormones and RNAi for induced maturation of Penaeus monodon

About 80 years ago, the neurosecretory eyestalk structures and their role in endocrine regulation was recognized in crustaceans. After the recognition it took half a century to identify the first peptide hormone. Till date a large number of homologous peptides of crustacean hyperglycaemic hormone and moult-inhibiting hormone have been identified, consequently they are called the CHH family hormones. This family comprises of highly multifunctional peptides which according to sequences and precursor structures can be divided into two subfamilies, type-I (CHH/ITP) and II (MIH, MOIH, VIH/GIH) (Webster et al., 2012). The XO-SG complex has been the major site of the two subfamilies. The advent of molecular techniques resulted in the characterization of different precursors of CHH, MIH and GIH; these hormones consist of a signal peptide, but only the preprohormone of CHHs contain a precursor- related peptide (CPRP) located between the signal and the mature hormone (Weidemann et al., 1989; Klein et al., 1993b; De Kleijn and Van Herp, 1995). The essentialities of the gene structure comply with the functions of the CHH family hormones. The CHH family hormone functions are inhibitory as well as stimulatory in the process of reproduction and maturation

Trial of recombinant follicle-stimulating hormone pretreatment for gnrh-induced fertility in patients with congenital hypogonadotropic hypogonadism.

CONTEXT AND OBJECTIVE: The optimal strategy for inducing fertility in men with congenital hypogonadotropic hypogonadism (CHH) is equivocal. Albeit a biologically plausible approach, pretreatment with recombinant FSH (rFSH) before GnRH/human chorionic gonadotropin administration has not been sufficiently assessed. The objective of the study was to test this method. DESIGN AND SETTING: This was a randomized, open-label treatment protocol at an academic medical center. PATIENTS AND INTERVENTIONS: GnRH-deficient men (CHH) with prepubertal testes (<4 mL), no cryptorchidism, and no prior gonadotropin therapy were randomly assigned to either 24 months of pulsatile GnRH therapy alone (inducing endogenous LH and FSH release) or 4 months of rFSH pretreatment followed by 24 months of GnRH therapy. Patients underwent serial testicular biopsies, ultrasound assessments of testicular volume, serum hormone measurements, and seminal fluid analyses. RESULTS: rFSH treatment increased inhibin B levels into the normal range (from 29 ± 9 to 107 ± 41 pg/mL, P < .05) and doubled testicular volume (from 1.1 ± 0.2 to 2.2 ± 0.3 mL, P < .005). Histological analysis showed proliferation of both Sertoli cells (SCs) and spermatogonia, a decreased SC to germ cell ratio (from 0.74 to 0.35), and SC cytoskeletal rearrangements. With pulsatile GnRH, the groups had similar hormonal responses and exhibited significant testicular growth. All men receiving rFSH pretreatment developed sperm in their ejaculate (7 of 7 vs 4 of 6 in the GnRH-only group) and showed trends toward higher maximal sperm counts. CONCLUSIONS: rFSH pretreatment followed by GnRH is successful in inducing testicular growth and fertility in men with CHH with prepubertal testes. rFSH not only appears to maximize the SC population but also induces morphologic changes, suggesting broader developmental roles.

Gonadotrophin replacement for induction of fertility in hypogonadal men.

Congenital hypogonadotrophic hypogonadism (CHH) is a rare form of infertility caused by deficient secretion or action of gonadotrophin-releasing hormone. There is no consensus regarding the optimal approach to fertility treatment in CHH men. In most cases, appropriate hormonal treatment with human chorionic gonadotrophin with or without follicle stimulating hormone will induce testicular development, spermatogenesis and fertility. Recent studies have examined sequential treatment with FSH pre-treatment to optimize fertility outcomes in severely affected CHH patients. This paper reviews historical and recent literature to summarize the current evidence on therapeutic approaches for CHH men seeking fertility.

Use and records of child health handbook focused on growth and development

Objective To evaluate the use and records of the Child Health Handbook (CHH), especially growth and development. Method Cross-sectional study with 358 mother-child pairs registered in 12 Primary Health Centers (PHCs) of a small municipality. Mothers were interviewed at the PHC from February to April 2013 using a questionnaire. Data analysis was done using WHO Anthro software, Epi InfoTM and Stata. Results Fifty-three percent of the mothers were carrying the CHH at the time of the interview, similar to the proportion of mothers who were instructed to bring the CHH to health appointments. Annotations in the CHH during the visits were reported by 49%. The vaccination schedule was completed in 97% of the CHH, but only 9% and 8% of the CHH, respectively, contained growth charts and properly completed developmental milestones. Conclusion Low rates of use and unsatisfactory record-keeping in the CHH reinforce the need for investment in professional training and community awareness for the CHH to become an effective instrument of promotion of child health.

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.

Microscopic study of He2-SF6 trimers

The He2-SF6 trimers, in their different He isotopic combinations, are studied in the framework of both the correlated Jastrow approach and the correlated hyperspherical harmonics (CHH) expansion method. The energetics and structure of the He-SF6 dimers are analyzed, and the existence of a characteristic rotational band in the excitation spectrum is discussed, as well as the isotopic differences. The binding energies and the spatial properties of the trimers, in their ground and lowest lying excited states, obtained by the Jastrow ansatz are in excellent agreement with the results of the converged CHH expansion. The introduction of the He-He correlation makes all trimers bound by largely suppressing the short range He-He repulsion. The structural properties of the trimers are qualitatively explained in terms of the shape of the interactions, Pauli principle, and masses of the constituents.

Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment.

Objective: To evaluate the degree of E-2 deficiency in male congenital hypogonadotropic hypogonadism (CHH), and its response to different hormonal treatments.Design: Retrospective and prospective studies.Setting: Academic institution.Patient(s): Untreated or treated CHH, healthy men, untreated men with Klinefelter syndrome (KS). Intervention(s): Serum sex hormone-binding globulin (SHBG) and total E-2 (TE2) as well as bioavailable (BE2) and free (FE2) levels were measured and determined.Main Outcome Measure(s): Total, bioavailable, and free testosterone, TE2, BE2, FE2 were compared in normal men, untreated and treated CHH and in untreated KS.Result(s): TE2, BE2, and FE2 levels were very significantly lower in untreated patients with CHH (n = 91) than in controls (n = 63) and in patients with KS (n = 45). The TE2 correlated positively with serum total T in patients with CHH. The TE2 also correlated very positively with serum LH in the combined population of patients with CHH and healthy men, suggesting that low E-2 levels in CHH are due to severe LH-driven T deficiency. All fractions of circulating E-2 were very significantly higher in patients with CHH receiving T enanthate (n = 101) or the FSH-hCG combination (n = 88) than in untreated patients with CHH. Contrary to dihydrotestosterone (DHT), both T enanthate and combined FSH-hCGtherapy significantly and prospectively increased TE2 levels in patients with CHH.Conclusion(s): Contrary to KS, the male hypogonadism observed in CHH is associated with profound E-2 deficiency, which can be overcome by aromatizable androgen or combined gonadotropin therapy. (Fertil Steril (R) 2011; 95: 2324-29. (C) 2011 by American Society for Reproductive Medicine.)

Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.

Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation.

Hormonal control of spermatogenesis in men: therapeutic aspects in hypogonadotropic hypogonadism.

During the first two trimesters of intrauterine life, fetal sex steroid production is driven by maternal human chorionic gonadotropin (hCG). The HPG axis is activated around the third trimester and remains active for the first 6-months of neonatal life. This so-called mini-puberty is a developmental window that has profound effects on future potential for fertility. In early puberty, GnRH secretion is reactivated first at night and then night and day. Pulsatile GnRH stimulates both LH and FSH, which induce maturation of the seminiferous tubules and Leydig cells. Congenital hypogonadotropic hypogonadism (CHH) results from GnRH deficiency. Men with CHH lack the mini-pubertal and pubertal periods of Sertoli Cell proliferation and thus present with prepubertal testes (<4mL) and low inhibin serum levels --reflecting diminished SC numbers. To induce full maturation of the testes, GnRH-deficient patients can be treated with either pulsatile GnRH, hCG or combined gonadotropin therapy (FSH+hCG). Fertility outcomes with each of these regimens are highly variable. Recently, a randomized, open label treatment study (n=13) addressed the question of whether a sequential treatment with FSH alone prior to LH and FSH (via GnRH pump) could enhance fertility outcomes. All men receiving the sequential treatment developed sperm in the ejaculate, whereas 2/6 men in the other group remained azoospermic. A large, multicenter clinical trial is needed to definitively prove the optimal treatment approach for severe CHH.

Identifying the unmet health needs of patients with congenital hypogonadotropic hypogonadism using a web-based needs assessment: implications for online interventions and peer-to-peer support.

BACKGROUND: Patients with rare diseases such as congenital hypogonadotropic hypogonadism (CHH) are dispersed, often challenged to find specialized care and face other health disparities. The internet has the potential to reach a wide audience of rare disease patients and can help connect patients and specialists. Therefore, this study aimed to: (i) determine if web-based platforms could be effectively used to conduct an online needs assessment of dispersed CHH patients; (ii) identify the unmet health and informational needs of CHH patients and (iii) assess patient acceptability regarding patient-centered, web-based interventions to bridge shortfalls in care. METHODS: A sequential mixed-methods design was used: first, an online survey was conducted to evaluate health promoting behavior and identify unmet health and informational needs of CHH men. Subsequently, patient focus groups were held to explore specific patient-identified targets for care and to examine the acceptability of possible online interventions. Descriptive statistics and thematic qualitative analyses were used. RESULTS: 105 male participants completed the online survey (mean age 37 ± 11, range 19-66 years) representing a spectrum of patients across a broad socioeconomic range and all but one subject had adequate healthcare literacy. The survey revealed periods of non-adherence to treatment (34/93, 37%) and gaps in healthcare (36/87, 41%) exceeding one year. Patient focus groups identified lasting psychological effects related to feelings of isolation, shame and body-image concerns. Survey respondents were active internet users, nearly all had sought CHH information online (101/105, 96%), and they rated the internet, healthcare providers, and online community as equally important CHH information sources. Focus group participants were overwhelmingly positive regarding online interventions/support with links to reach expert healthcare providers and for peer-to-peer support. CONCLUSION: The web-based needs assessment was an effective way to reach dispersed CHH patients. These individuals often have long gaps in care and struggle with the psychosocial sequelae of CHH. They are highly motivated internet users seeking information and tapping into online communities and are receptive to novel web-based interventions addressing their unmet needs.

The health promotion model and rare disease patients : a mixed methods study examining adherence to treatment in men with congenital hypogonadotropic hypogonadism

Rare diseases are typically chronic medical conditions of genetic etiology characterized by low prevalence and high complexity. Patients living with rare diseases face numerous physical, psychosocial and economic challenges that place them in the realm of health disparities. Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder characterized by absent puberty and infertility. Little is known about the psychosocial impact of CHH on patients or their adherence to available treatments. This project aimed to examine the relationship between illness perceptions, depressive symptoms and adherence to treatment in men with CHH using the nursing-sensitive Health Promotion Model (HPM). A community based participatory research (CBPR) framework was employed as a model for empowering patients and overcoming health inequities. The study design used a sequential, explanatory mixed-methods approach. To reach dispersed CHH men, we used web-based recruitment and data collection (online survey). Subsequently, three patient focus groups were conducted to provide explanatory insights into the online survey (i.e. barriers to adherence, challenges of CHH, and coping/support) The online survey (n=101) revealed that CHH men struggle with adherence and often have long gaps in care (40% >1 year). They experience negative psychosocial consequences because of CHH and exhibit significantly increased rates of depression (p<0.001). Focus group participants (n=26) identified healthcare system, interpersonal, and personal factors as barriers to adherence. Further, CHH impacts quality of life and impedes psychosexual development in these men. The CHH men are active internet users who rely on the web forcrowdsourcing solutions and peer-to-peer support. Moreover, they are receptive to web-based interventions to address unmet health needs. This thesis contributes to nursing knowledge in several ways. First, it demonstrates the utility of the HPM as a valuable theoretical construct for understanding medication adherence and for assessing rare disease patients. Second, these data identify a range of unmet health needs that are targets for patient-centered interventions. Third, leveraging technology (high-tech) effectively extended the reach of nursing care while the CBPR approach and focus groups (high-touch) served as concurrent nursing interventions facilitating patient empowerment in overcoming health disparities. Last, these findings hold promise for developing e-health interventions to bridge identified shortfalls in care and activating patients for enhanced self- care and wellness -- Les maladies rares sont généralement de maladies chroniques d'étiologie génétique caractérisées par une faible prévalence et une haute complexité de traitement. Les patients atteints de maladies rares sont confrontés à de nombreux défis physiques, psychosociaux et économiques qui les placent dans une posture de disparité et d'inégalités en santé. L'hypogonadisme hypogonadotrope congénital (CHH) est un trouble endocrinien rare caractérisé par l'absence de puberté et l'infertilité. On sait peu de choses sur l'impact psychosocial du CHH sur les patients ou leur adhésion aux traitements disponibles. Ce projet vise à examiner la relation entre la perception de la maladie, les symptômes dépressifs et l'observance du traitement chez les hommes souffrant de CHH. Cette étude est modélisée à l'aide du modèle de la Promotion de la santé de Pender (HPM). Le cadre de l'approche communautaire de recherche participative (CBPR) a aussi été utilisé. La conception de l'étude a reposé sur une approche mixte séquentielle. Pour atteindre les hommes souffrant de CHH, un recrutement et une collecte de données ont été organisées électroniquement. Par la suite, trois groupes de discussion ont été menées avec des patients experts impliqués au sein d'organisations reliés aux maladies rares. Ils ont été invités à discuter certains éléments additionnels dont, les obstacles à l'adhésion au traitement, les défis généraux de vivre avec un CHH, et l'adaptation à la maladie en tenant compte du soutien disponible. Le sondage en ligne (n = 101) a révélé que les hommes souffrant de CHH ont souvent de longues périodes en rupture de soins (40% > 1 an). Ils vivent des conséquences psychosociales négatives en raison du CHH et présentent une augmentation significative des taux de dépression (p <0,001). Les participants aux groupes de discussion (n = 26) identifient dans l'ordre, les systèmes de soins de santé, les relations interpersonnelles, et des facteurs personnels comme des obstacles à l'adhésion. En outre, selon les participants, le CHH impacte négativement sur leur qualité de vie générale et entrave leur développement psychosexuel. Les hommes souffrant de CHH se considèrent être des utilisateurs actifs d'internet et comptent sur le web pour trouver des solutions pour trouver des ressources et y recherchent le soutien de leurs pairs (peer-to-peer support). En outre, ils se disent réceptifs à des interventions qui sont basées sur le web pour répondre aux besoins de santé non satisfaits. Cette thèse contribue à la connaissance des soins infirmiers de plusieurs façons. Tout d'abord, elle démontre l'utilité de la HPM comme une construction théorique utile pour comprendre l'adhésion aux traitements et pour l'évaluation des éléments de promotion de santé qui concernent les patients atteints de maladies rares. Deuxièmement, ces données identifient une gamme de besoins de santé non satisfaits qui sont des cibles pour des interventions infirmières centrées sur le patient. Troisièmement, méthodologiquement parlant, cette étude démontre que les méthodes mixtes sont appropriées aux études en soins infirmiers car elles allient les nouvelles technologies qui peuvent effectivement étendre la portée des soins infirmiers (« high-tech »), et l'approche CBPR par des groupes de discussion (« high-touch ») qui ont facilité la compréhension des difficultés que doivent surmonter les hommes souffrant de CHH pour diminuer les disparités en santé et augmenter leur responsabilisation dans la gestion de la maladie rare. Enfin, ces résultats sont prometteurs pour développer des interventions e-santé susceptibles de combler les lacunes dans les soins et l'autonomisation de patients pour une meilleure emprise sur les auto-soins et le bien-être.

Comment on reversal of hypogonadotropic hypogonadism in a Chinese cohort.

The reversal of congenital hypogonadotropic hypogonadism (CHH) is a relatively recent phenomenon that has gained increasing attention over the past 10 years. Yet to date, only one prospective study has been conducted estimating that 10% (95% confidence interval [CI]: 2%-18%) of cases undergo reversal. [1] Other retrospective studies have reported rates in the range of 5%-8% [2],[3] and a recent study showed 44/308 (14%, 95% CI: 11%-19%) CHH patients underwent reversal. [4] Moreover, a time-to-event analysis in this large cohort revealed a lifetime reversal incidence of 22%. The article by Mao and colleagues presented in this issue is a meaningful contribution to our understanding of reversal as it examines the largest retrospective cohort to date. [5] Interestingly, they report the rate of reversal as 5% (95% CI: 3%-8%) in this Chinese cohort. It is difficult to reconcile the discrepancies in rates of reversibility and direct comparisons are hampered by the variable definitions employed. Using a novel definition for reversal (i.e, either endogenous testosterone (T) >270 ng dl−1 , serum T gradually increasing above 150 ng dl−1 with increased testicular volume, or normal spontaneous sperm production/normal erectile function/ejaculation), Mao and colleagues posit that testicular size and triptorelin-stimulated LH levels are reliable predictive factors for reversal. However, these cannot be considered as hard and fast rules for predicting reversal as the groups intersect - akin to the overlap observed between CHH patients and those with delayed puberty. Indeed, the fact that approximately half (44%, 95% CI: 25%-66%) of the reversal patients in the study by Mao et al.[5] were diagnosed between 17 and 19 years of age, underscores the challenge in differentiating CHH from extreme normal variants of puberty. This study further lends credence the recently reported observations that reversals may relapse. [4],[6] The notion that reversal may not be lasting highlights the vulnerability of the reproductive axis among CHH patients. While the mechanism(s) for relapse are unclear, it seems plausible that environmental, metabolic or psychiatric stressors could contribute. The factors that Mao and colleagues identify as significantly different in cases of reversal, were not informative for identifying those cases that relapsed back to a hypogonadal state. Notably, reversal has been reported in probands harboring mutations in genes underlying CHH. [1],[3],[4],[6] Unfortunately, comprehensive genetic screening on the Chinese cohort is not available. The reversal phenomenon is fascinating for its glimpse into the plasticity of the neuroendocrine control of reproduction. Future directions will almost certainly include investigation of specific genetic signatures and novel biomarkers for predicting reversal (and relapse). Yet CHH is a rare condition and to fully elucidate the biology of reversible CHH, it will be important to harmonize definitions of what constitutes a reversal, carefully phenotype patients and chart the natural history of their CHH. In this way, this unique human disease model may offer further insights into the control of human reproduction and provide opportunities to translate discoveries into enhanced approaches to improve the care and quality of life for these patients.

Psychosexual development in men with congenital hypogonadotropic hypogonadism on long-term treatment: a mixed methods study.

INTRODUCTION: Congenital hypogonadotropic hypogonadism (CHH) is a rare, genetic, reproductive endocrine disorder characterized by absent puberty and infertility. Limited information is available on the psychosocial impact of CHH and psychosexual development in these patients. AIM: The aim of this study was to determine the impact of CHH on psychosexual development in men on long-term treatment. METHODS: A sequential mixed methods explanatory design was used. First, an online survey (quantitative) was used to quantify the frequency of psychosexual problems among CHH men. Second, patient focus groups (qualitative) were conducted to explore survey findings in detail and develop a working model to guide potential nursing and interdisciplinary interventions. MAIN OUTCOME MEASURES: Patient characteristics, frequency of body shame, difficulty with intimate relationships, and never having been sexually active were assessed. Additionally, we collected subjective patient-reported outcomes regarding the impact of CHH on psychological/emotional well-being, intimate relationships, and sexual activity. RESULTS: A total of 101 CHH men on long-term treatment (>1 year) were included for the analysis of the online survey (mean age 37 ± 11 years, range 19-66, median 36). Half (52/101, 51%) of the men had been seen at a specialized academic center and 37/101 (37%) reported having had fertility-inducing treatment. A high percentage of CHH men experience psychosexual problems including difficulty with intimate relationships (70%) and body image concerns/body shame (94/101, 93%), and the percentage of men never having been sexually active is five times the rate in a reference group (26% vs. 5.4%, P < 0.001). Focus groups revealed persisting body shame and low self-esteem despite long-term treatment that has lasting impact on psychosexual functioning. CONCLUSIONS: CHH men frequently experience psychosexual problems that pose barriers to intimate relationships and initiating sexual activity. These lingering effects cause significant distress and are not ameliorated by long-term treatment. Psychosexual assessment in CHH men with appropriate psychological support and treatment should be warranted in these patients. Dwyer AA, Quinton R, Pitteloud N, and Morin D. Psychosexual development in men with congenital hypogonadotropic hypogonadism on long-term treatment: A mixed methods study. Sex Med 2015;3:32-41.

Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment.

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ∼50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRH-synthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ∼10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.