Congenital Hypogonadotropic Hypogonadism Patients Research Articles

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

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? Both parameters lack the specificity to discriminate CDGP from CHH. 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. 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. 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. 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. As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here. 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. 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. N/A.

Identification of gene variants in a cohort of hypogonadotropic hypogonadism: Diagnostic utility of custom NGS panel and WES in unravelling genetic complexity of the disease

Congenital hypogonadotropic hypogonadism (CHH) is caused by dysfunction of hypothalamic gonadotropic-releasing hormone (GnRH) axis. The condition is both clinically and genetically heterogeneous with more than 40 genes implicated in pathogenesis.The goal of the present study was to identify causative mutations in CHH individuals employing 2 step procedure with a targeted NGS panel as first-line diagnostics and subsequently whole exome sequencing in unsolved cases.Known or novel potentially deleterious variants were found in 28 out of 47 tested CHH patients. Molecular diagnosis was reached in 19/47 CHH cases. In 13 cases monogenic variants were identified in ANOS1, FGFR1, GNRHR, CHD7, SOX10, and PROKR2, while 6 patients showed digenic or trigenic inheritance patterns. The achieved diagnostic rate was comparable to other studies on genetics of CHH.By evaluating and reporting more patients with CHH we make progress in unravelling its genetic complexity and move a step closer to personalised medicine.

Nectin-like molecule 2, a necessary sexual maturation regulator, participates in congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetically heterogeneous disorder. We aimed to determine the prevalence and pathogenesis of NECL2 (Nectin-like molecule 2) variants in a cohort of female patients with CHH. We sequenced and determined the prevalence of NECL2 variants in 68 female patients with CHH and 243 healthy controls collected from an academic medical center. Further cellular and animal studies were performed to verify the pathogenicity of the mutations. Necl2 knockout female mice were generated, and their puberty development was observed. A novel NECL2 variant (c.1052_1060del, p.Thr351_Thr353del) was detected in 4 of 68 (5.9%) patients with CHH. Its prevalence was significantly higher in CHH patients than in healthy controls (0%). At the cellular level, the necl2 variant leads to a decrease in gonadotropin-releasing hormone. In animal models, we found that the Necl2 protein was expressed in the hypothalamus, especially in the ventromedial hypothalamic nucleus of mice. Necl2 knockout female mice showed delayed puberty and an irregular estrous cycle, consistent with CHH patient phenotypes. Our findings predict that NECL2 may be a new candidate gene for CHH and that the NECL2 protein plays a critical role in the progression of puberty development.

Gonadotropin-Induced Spermatogenesis in CHH Patients with Cryptorchidism

Congenital hypogonadotropic hypogonadism (CHH) patients with cryptorchidism history usually have poor spermatogenesis outcome, while researches focusing on this population are rare. This study retrospectively evaluated gonadotropin-induced spermatogenesis outcome in CHH patients with cryptorchidism (n = 40). One hundred and eighty-three CHH patients without cryptorchidism were served as control. All patients received combined gonadotropins therapy (HCG and HMG) and were followed up for at least 6 months. The median follow-up period was 24 (15, 33) months (totally 960 person-months). Sperm (>0/ml) initially appeared in semen at a median of estimated 24 months (95% confidence interval (CI) 17.8–30.2). Twenty (20/40, 50%) patients succeeded in producing sperms, and the average time to produce first sperm was 19 ± 8 months. Five pregnancies were achieved in 9 (5/9, 56%) couples who desired for children. Compared with CHH patients without cryptorchidism (n = 183), cryptorchid patients had longer median time for sperm appearance in semen (24 months vs. 15 months, P < 0.001), lower rate of spermatogenesis (50% vs. 67%, P=0.032), and lower mean sperm concentration (1.9 (0.5, 8.6) million/ml vs. 11.1(1.0, 25.0) million/ml, P=0.006) at the last visit. In conclusion, CHH patients with cryptorchidism require a longer period for gonadotropin-induced spermatogenesis. The successful rate and sperm concentration were lower than patients without cryptorchidism.

Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder mostly characterized by gonadotropins release and/or action deficiencies. Both isolated (idiopathic hypogonadotropic hypogonadism) and syndromic (Kallmann) forms are identified depending on the olfactory ability. Clinical and genetic heterogeneities of CHH have been widely explored, thus improving our understanding of the disease's pathophysiology. This work aims to (1) provide a detailed clinical and hormonal description of normosmic CHH patients and (2) identify the mutation linked to the studied phenotype. We investigated three affected patients with normosmic CHH, belonging to a consanguineous Tunisian family. Patients underwent an insulin-induced hypoglycemia test. We performed whole exome sequencing to identify the causal mutation. At first diagnosis, a total gonadotropic deficiency was identified in all patients. The insulin-induced hypoglycemia test has also revealed a reduced cortisol secretion and complete growth hormone deficiency. At 20.8years, one female exhibited a spontaneous recovery of the hypothalamic-pituitary-adrenal axis function, unlike her affected siblings who still depend on corticosteroid replacement therapy. Herein, we identified a novel homozygous nonstop mutation (c.1195T>C) in KISS1R gene in all affected subjects. This mutation led to the substitution of the physiologic stop codon by an arginine (p.X399R). Our study highlights the importance of the KISS1R signaling, in gonadotropin-releasing hormone neurons, in the control of reproductive function. Additionally, our data suggests a complex central and peripheral metabolic control of puberty, through the hypothalamic KISS1R signaling. We suggest a mutual link between the hypothalamic-pituitary-gonadal, -adrenal, and -somatotropic axes.

MON-LB051 Non-inferiority Clinical Trial on Gonadotropinversus Pulsatile Gonadotropin-releasing Hormone Infusion Therapy in Male Adolescent Patient with Congenital Hypogonadotropic Hypogonadism

Context We investigate the efficacy and safety of non-inferiority clinical trial for human chorionic gonadotropin/ human menopausal gonadotropin (HCG/HMG) versus pulsatile gonadotropin-releasing hormone (GnRH) which has not been evaluated on non-inferiority clinical trial in puberty boys with CHH. Objective To compare the efficacy and security of two different treatments in male adolescent patient with congenital hypogonadotropic hypogonadism (CHH) . To explore the standardization of early treatment and it is possible clinical recommended regimen. Methods For this prospective cohort nonrandomized controlled study, male adolescent CHH patients were recruited and categorized into HCG/HMG(group 1) and GnRH (group 2) groups. All patients were treated for 3-12months. The study was divided into research period (3 months of treatment) and extension period (3 to 12 months of treatment). Testicular volume (TV), penile length(PL), blood sex hormones levels, height, body weight, and other related laboratory indices were measured and evaluated. In this study, we observe the therapeutic effect within 3 months and also collect partial extended period data for providing further research experience. Results All CHH patients were treated for over 3 months. At the beginning, the average age of patients, the testicular volume, penile length, penile diameter in group 1 and group 2 were 15.3±1.9 years VS 14.2±1.5 years, 2.5±1.4ml VS 2.7±1.5ml, 4.8±1.3cm VS 4.2±1.4cm and 1.6±0.4cm VS 1.5±0.4cm. The difference of two groups was not statistically significant. After 3 months treatment, the testicular volume, penile length, penile diameter, the growth of testicular volume, the growth of penile length and the growth of penile diameter in group 1 and group 2 were 5.1±2.7ml VS 4.6±2.7ml , 6.9±1.7cm VS 5.1±1.6cm, 2.5±0.5cm VS 1.9±0.6cm,2.0±1.6 cm 和1.0±0.8cm, 0.9±0.5cmand0.3±0.4cm. The difference of two groups was not statistically significant. There was no significant difference in height, body weight, or BMI between the two treatments. Based on the principles of hypothesis-test, mean value M-0.25625, standard error(SE) = 0.69319,M±1.96, Se=-0.25625±1.3586524,(-1.161,1.10). The growth differential of testicular volume between group 1 and group 2 was less than 2ml in (P<0.05) . It can be inferred that group 1 is not inferior to group 2. There was no significant difference in efficacy comparison in some of the patients were treated after 6-12 months in both groups. There was no significant difference in side effects in both groups. Conclusions In this clinical trial, 3 months was an observation period. Short-term therapeutic indicated adolescent patients with CHH were effectively treated with HCG/HMG and GnRH. We discovered that the effect of HCG/HMG was as good as GnRH in treating adolescent boys with CHH. This therapeutic schedule can be used in more patients. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

MON-244 GnRH Test Does Not Efficiently Discriminate Congenital Isolated Hypogonadotropic Hypogonadism from Constitutional Delay of Growth and Puberty in Males

Context: Delayed puberty can be due to either constitutional delay of growth and puberty (CDGP) or congenital hypogonadotropic hypogonadism (CHH). Differentiating between the two conditions either clinically or using current hormonal testing is difficult. GnRH test is currently used in many centers to differentiate CDGP from CHH but its diagnostic performance was not assessed in a significant number of CHH patients. Objective: To compare gonadotropin responses to GnRH challenge between CHH and C and to assess the diagnostic performance of this test in large cohorts of CHH and CDGP. Subjects: We included 127 men with CHH (68 Kallmann Syndrome (KS) and 69 normosmic CHH; age: 25.5±9.9 y), 74 men with CDGP (14.9±1.0 y) not treated, 31 control (C) men (25.9±5.2 y). Methods: Testicular volume (TV) was measured. Basal testosterone and inhibin B (IB, limit of detection: 3 pg/mL) were measured using sensitive immunoassays. Intravenous injection of 100 μg GnRH was performed. Serum FSH and LH were measured (at -15, 0, 15, 30, 60, and 120 min) using sensitive immunoradiometric assays with a detection limit of 0.05 IU/L for both gonadotropins. Results (mean±SD, [range]): Testosterone levels (ng/mL) were: C, 6.5±1.2 [4.2-8.7]; CHH/KS, 0.5±0.4 [0.0-2.1]; CDGP, 0.6±0.6 [0.0-2.5]. Testicular volumes (mL) were respectively in CHH/KS and CDGP: 3.1±2.8 [0.1-13.5] and 4.5±2.7 [0.7-10]. LH basal and peaks (IU/L) were: C, basal: 4.2±0.9 [2.9-6.1], peak 17.9±3.7 [11.1-26.0]; CHH/KS, basal 0.8±1.0 [0.1-4.2], peak: 6.9±7.8 [0.1-41.5]; CDGP, basal: 1.3±0.8 [0.1-3.7]; peak: 13.9±6.3 [4.0-33.4]. In 25/127 (21%) of CHH/KS, we found an overlapping in serum LH peaks levels when compared to C. Importantly, in 47% (60/127) of CHH/KS patients, GnRH-induced LH peaks overlapped with LH peak values observed in CDGP. However, none of the patients with CDGP had LH peak values below 4.0 IU/L while 68/127 (53%) of those with CHH/KS had LH peak levels below this threshold. In CHH/KS and CDGP, serum IB were respectively (58±64 [3-311] and 164±97 [35-630]). In 59% of untreated CHH/KS patients, serum IB overlapped with CDGP. In CHH, we found a significant positive correlation between LH peak and TV (r=0.41; p < 0.0001) and a stronger positive correlation between LH peak and IB (r=0.49; p< 0.0001). Conclusion: In both CHH/KS and CDGP, the ranges of GnRH induced LH peaks were very wide and a strong overlapping was found between the three groups studied. Both LH peak and IB were correlated with the severity of gonadotropin deficiency as reflected by TV. The GnRH challenge test is not efficient enough to discriminate CHH/KS from CDGP but very weak LH responses (4 IU/L) were specifically observed in CHH/KS. Diagnosis efficiency of serum IB will also be discussed.

Testosterone replacement in congenital hypogonadotropic hypogonadism maintains bone density but has only limited osteoanabolic effects.

Congenital hypogonadotropic hypogonadism (CHH) is a rare condition characterized by complete sex steroid deficiency. Therefore, CHH is a unique human model to study the impact of long-term testosterone replacement therapy (TRT) on bone. In this single-center retrospective observational study, we assessed the long-term impact of TRT on femoral and lumbar bone mineral density (BMD) in adult CHH men. A total of 25 patients with CHH were included. Femoral and lumbar BMD was assessed by dual-energy X-ray absorptiometry (DEXA) and reported as T-scores. In six patients (treatment-naive group), BMD was measured before start of TRT. The other 19 (pre-treated group) had received TRT for a median duration of 7years (range 1-41years) before first BMD measurement. Age at which TRT was started ranged from 12 to 57years old. Median time between first and last DEXA scan was 11years (range 2-28). At the first DEXA scan, 83% and 61% of CHH patients had lumbar and femoral osteopenia/osteoporosis, respectively. In the treatment-naive group, the increase in lumbar T-score was 2.19±0.13 (mean ± SEM, p<0.01 between first and last DEXA scan) and 1.47±0.29 at femoral level (p<0.001). For the pre-treated group, the increase in lumbar and femoral T-score was 0.77±0.17 (p<0.001) and 0.19±0.12 (p=0.13), respectively. However, lumbar and femoral osteopenia/osteoporosis persisted in 61% and 48% of CHH patients even after several years of continuous TRT. Additionally, BMD clearly decreased in patients who interrupted TRT. Despite modest improvement after starting TRT, BMD remains in the osteopenic/osteoporotic range in most patients with CHH. However, prolonged TRT prevents further bone loss, both at lumbar and femoral level.

Assisted reproductive techniques with congenital hypogonadotropic hypogonadism patients: a systematic review and meta-analysis

BackgroundAfter hormonal replacement therapy (HRT) including androgen replacement or sequential therapy of estrogen and progesterone, The combination of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) and pulsatile GnRH, is not sufficient to produce sufficient gametes in some patients with Congenital hypogonadotropic hypogonadism (CHH). A Systematic review and meta-analysis was performed to determine that assisted reproductive techniques (ART) can effectively treat different causes of infertility.MethodsTo determine the effect of ART on fertility of CHH patients and investigate whether outcomes are similar to infertility due to other causes, we conducted a systematic review and meta-analysis of retrospective trials.Clinical trials were systematically searched in Medline, Embase, and the Cochrane central register of controlled trials databases. The keywords and major terms covered “hypogonadotropic hypogonadism”, “kallmann syndrome”, “assisted reproductive techniques”, “intrauterine insemination”, “intracytoplasmic sperm injection”, “testicular sperm extraction”, “in vitro fertilization”, “embryo transplantation” and “intra-Fallopian transfer”.ResultsA total of 388 pregnancies occurred among 709 CHH patients who received ART (effectiveness 46, 95% confidence interval 0.39 to 0.53) in the 20 studies we included. The I2 in trials assessing overall pregnancy rate (PR) per embryo transfer (ET) cycle was 73.06%. Similar results were observed in subgroup analysis by different gender. Regression indicates pregnancy rate decreases with increasing age. Fertilization, implantation and live birth rates (72, 36 and 40%) showed no significant differences as compared to infertility due to other causes.ConclusionsDespite CHH patients usually being difficult to generate gametes, their actual chances of fertility are similar to subjects with other non-obstructive infertility. ART is a suitable option for CHH patients who do not conceive after long-term gonadotropin treatment.

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism.

Pulsatile gonadotropin-releasing hormone (GnRH) may induce spermatogenesis in most patients with congenital hypogonadotropic hypogonadism (CHH) by stimulating gonadotropin production, while the predictors for a pituitary response to pulsatile GnRH therapy were rarely investigated. Therefore, the aim of our study is to investigate predictors of the pituitary response to pulsatile GnRH therapy. This retrospective cohort study included 82 CHH patients who received subcutaneous pulsatile GnRH therapy for at least 1 month. Patients were categorized into poor or normal luteinizing hormone (LH) response subgroups according to their LH level (LH <2 IU l−1 or LH ≥2 IU l−1) 1 month into pulsatile GnRH therapy. Gonadotropin and testosterone levels, testicular size, and sperm count were compared between the two subgroups before and after GnRH therapy. Among all patients, LH increased from 0.4 ± 0.5 IU l−1 to 7.5 ± 4.4 IU l−1 and follicle-stimulating hormone (FSH) increased from 1.1 ± 0.9 IU l−1 to 8.8 ± 5.3 IU l−1. A Cox regression analysis showed that basal testosterone level (β = 0.252, P = 0.029) and triptorelin-stimulated FSH60min (β = 0.518, P = 0.01) were two favorable predictors for pituitary response to GnRH therapy. Nine patients (9/82, 11.0%) with low LH response to GnRH therapy were classified into the poor LH response subgroup. After pulsatile GnRH therapy, total serum testosterone level was 39 ± 28 ng dl−1 versus 248 ± 158 ng dl−1 (P = 0.001), and testicular size was 4.0 ± 3.1 ml versus 7.9 ± 4.5 ml (P = 0.005) in the poor and normal LH response subgroups, respectively. It is concluded that higher levels of triptorelin-stimulated FSH60minand basal total serum testosterone are favorable predictors of pituitary LH response to GnRH therapy.

Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants.

Congenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined. Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype-phenotype correlations were evaluated. Of the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01). Pathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.

KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.

Efficacy and Outcome Predictors of Gonadotropin Treatment for Male Congenital Hypogonadotropic Hypogonadism: A Retrospective Study of 223 Patients.

Gonadotropin induces masculinization and spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). However, large cohort studies for the efficacy and reliable predictors of this therapy need to be conducted. The aim of this study was to investigate the efficacy of gonadotropin treatment in a large cohort of male CHH patients and analyze putative predictors for successful spermatogenesis. This retrospective study included 223 CHH azoospermic patients without puberty development treated between 2005 and 2014. All patients received combined human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) and were followed up for >6 months (5109 person-months). Serum total testosterone level, testicular size, spermatogenesis, and pregnancy outcome were recorded at each visit. After gonadotropin therapy, testicular size was enlarged from 2.1 ± 1.6 to 8.1 ± 4.6 mL (P < 0.001) and serum total testosterone was elevated from 0.9 ± 0.5 to 15.1 ± 8.2 nmol/L (P < 0.001). Spermatogenesis (>0/mL) occurred at a median period of 15 months (95% confidence interval 13.5-16.5). Larger basal testicular volume (P = 0.012) and noncryptorchidism history (P = 0.028) are independent predictors for earlier sperm appearance. Sixty four percent (143/223) of patients succeeded in producing sperms and the average time for initial sperm detection was 14 ± 8 months. However, their sperm concentrations (11.7 [2.1, 24.4] million/mL) and sperm progressive motility (A + B 36.9% ± 20.2%) are significantly lower than World Health Organization standards. Of the 34 patients who desired for fathering children, 19 patients impregnanted their partners during the treatment. Gonadotropin therapy induces spermatogenesis in male CHH patients. A larger basal testicular size and noncryptorchidism history are favorable indicators for earlier spermatogenesis.

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%23 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.46 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.1346 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. COMPETING INTERESTS The authors declare no competing interests.

Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future.

The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime.

The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients.

Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families. Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.

Genetics of congenital hypogonadotropic hypogonadism in Denmark

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by incomplete/absent puberty caused by deficiency or defective action of gonadotropin-releasing hormone (GnRH). The phenotypic features of patients with CHH vary from genital hypoplasia and absent puberty to reversal of HH later in life. We examined the genetics and clinical features of CHH in Denmark. Forty-one male patients were screened for mutations in KAL1, FGFR1, FGF8, PROK2, PROKR2, GNRHR, TAC3, TACR3, and KISS1R. CHD7 was screened in two patients with hearing loss. In 12 patients, a molecular genetic cause for CHH was found. Four patients had mutations in KAL1 (C105VfsX13, C53X, ex5-8del, R257X), and five in FGFR1 (G97S, R209C, A512V, R646W, and c.1614C>T, (p.I538I), predicted to affect splicing). All 9 had severe HH (cryptorchidism and/or micropenis), and 2 had cleft lip/palate. One patient with a previously reported homozygous R262Q mutation in GNRHR displayed fascinating temporal variation in his phenotype. Two patients with hearing loss had CHD7 mutations (c.7832_7841del (p.K2611MfsX25) and c.2443-2A>C), confirming that CHH patients with CHARGE syndrome-associated features should be screened for mutations in CHD7.

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.

BackgroundPatients 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.MethodsA 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.Results105 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.ConclusionThe 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.

Computed Tomography of the Anterior Skull Base in Kallmann Syndrome Reveals Specific Ethmoid Bone Abnormalities Associated With Olfactory Bulb Defects

Kallmann syndrome (KS) is characterized by congenital hypogonadotropic hypogonadism (CHH) and an impaired sense of smell related to defective development of the olfactory system. The aim of the study was to use high-resolution computed tomography (CT) to detect specific abnormalities in the ethmoid bone region surrounding the olfactory bulbs in patients with KS. Thirty-seven KS patients were compared to normosmic CHH (nCHH) patients (n = 15) and controls (n = 30) of similar age. We conducted a prospective study in a single referral center. Subjects underwent CT in bone windows with axial, coronal, and sagittal reconstructions centered on the olfactory fossa (OF) and cribriform plate (CP). We characterized the OF structure by measuring OF height, width, and surface area and a series of angles. The CP foramina were counted bilaterally. Olfactory bulb magnetic resonance imaging, performed in parallel, was compared with CT findings. OF height, width, and surface area were all significantly lower in KS patients than in nCHH patients and controls (P < .0001). KS patients also had wider angles than nCHH patients and controls (P < .0001). KS subjects with olfactory bulb agenesis on magnetic resonance imaging or who harbored KAL1 mutations had the most marked changes in OF measurements and angles. Coronal OF height distinguished KS patients from controls with the best sensitivity and specificity. The mean number of CP foramina was similar in KS, nCHH, and control subjects. KS is associated with specific ethmoid bone abnormalities. The preserved number of CP foramina in KS patients suggests that the integrity of olfactory structures is not mandatory for their formation during fetal development or their maintenance in adult life.

Hypogonadotropic hypogonadism as a model of post-natal testicular anti-Müllerian hormone secretion in humans

The pituitary gonadodotropins are the main regulators of testicular hormonal secretion in humans. Hypogonadotropic hypogonadism (HH), characterized by the absence of secretion of endogenous gonadotropins is therefore a convenient model to asses the respective effects of luteinizing hormone (LH) (or human chorionic gonadotropin (hCG)), exogenous testosterone (T) and FSH on gonadal function. In order to investigate the hormonal control of AMH secretion in man, serum AMH levels were measured in adult patients with congenital HH (CHH) and with post-pubertal acquired HH (AHH) either untreated, during hCG or T therapy. In untreated CHH patients, serum AMH levels were significantly higher than in normal men and similar to those previously reported in prepubertal boys indicating the absence of pubertal maturation of Sertoli cells. In men with AHH, serum AMH levels were also significantly increased when compared to healthy men, but less than in CHH because a persistent testicular T secretion in these patients with less complete gonadotropin deficiency. The high AMH levels in AHH suggest that the post-pubertal suppression of AMH is a reversible phenomenon. In HH patients, hCG treatment induced an increase of plasma T associated with a dramatic decrease of serum AMH, whereas the similar increase in plasma T levels obtained with exogenous T induced only a partial decrease of serum AMH. This dissociation was related to the higher intratesticular T induced by hCG. Taken together, our results confirms the clinical relevance of previous data obtained in rodent models concerning the hormonal regulation of AMH secretion.