A Clinical Experience of Pubertal Induction in Female Patients With Congenital Hypogonadotropic Hypogonadism (CHH) From an Endo-ERN Referral Center

Abstract Female congenital hypogonadotropic hypogonadism (CHH) is a rare condition, with a strong genetic background, characterized by absent or incomplete pubertal development, for which inductive treatment with sex-hormone is required. Although the available data, mostly coming from studies in patients with Turner syndrome, indicate transdermal estradiol (TDE) as the first-choice formulation, no internationally validated therapeutic schemes are currently available. Furthermore, data on CHH patients are certainly lacking and there is no standard of care for pubertal induction in this specific population. The aim of our work was the retrospective analysis of the data from a collection of case reports of pubertal induction in CHH patients referred to our Center. Six patients underwent induction with transdermal estradiol (TDE) at the starting dose of 0.1µg/kg/day (night-time for the first 4-6 months), increased every 4-6 months up to the adult dose, for a mean period of 2.86 ± 0.45 ys. Micronized progesterone (200 mcg) was introduced at reaching of 50µg dose or if breakthrough bleeding occurred. Treatment was monitored through clinical and anthropometric evaluations at each dose modification. The average age of induction was 17.25 ± 1.41 ys, with each bone age> 13 ys. Three out of six patients already had a Tanner B2 stage at diagnosis. The mean times of pubertal advancement were respectively 1.3 ± 0.46 ys for the achievement of B3, 2.13 ± 0.29 ys for the B4 and 2.35 ± 0.77 ys for menarche; all the patients reached an adult breast conformation (B5) in 2.81 ± 0.28 ys. These data are consistent with physiological pubertal progress. All of them achieved adequate uterine development (medium longitudinal diameter 72.2 ± 3.37mm), except one patient with suboptimal development (54mm). The final height (FH) was adequate in all patients, with SDS FH +1.6 (-0.43 - +3.38), in spite of an average growth of 4.11 cm (2.5-6) during the induction period and a growth rate > 2cm/year only in 50% of patients. No side effects were reported, and individual compliance and satisfaction were quite high. This clinical experience suggests that the adopted regimen, consistent with current literature, guarantees excellent efficacy and safety. However, further studies are needed to identify the optimal treatment in adolescents with CHH, taking into account their higher age at the start of induction, the modest impact on growth and final stature, to focus on the specific clinical objectives in these patients

Download Full-text

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Acta Endocrinologica ◽

10.1530/eje-17-0749 ◽

2018 ◽

Vol 178 (3) ◽

pp. R55-R80 ◽

Cited By ~ 50

Author(s):

Luigi Maione ◽

Andrew A Dwyer ◽

Bruno Francou ◽

Anne Guiochon-Mantel ◽

Nadine Binart ◽

...

Keyword(s):

Genetic Counseling ◽

Next Generation Sequencing ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Kallmann Syndrome ◽

Incomplete Penetrance ◽

Next Generation ◽

Congenital Hypogonadotropic Hypogonadism ◽

Main Challenge ◽

Generation Sequencing

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women. However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation. These are genetic diseases that can be transmitted to patients’ offspring. Importantly, patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex; oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing and is increasingly being used in medical practice. Thus, it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission and also its role in incomplete penetrance and variable expressivity in a perspective of genetic counseling.

Download Full-text

MON-273 Retrospective Analysis of Gonadotropin-Mediated Pubertal Induction in Male Patients with Congenital Hypogonadotropic Hypogonadism (CHH)

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1809 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Biagio Cangiano ◽

Giovanni Goggi ◽

Fabiana Guizzardi ◽

Valeria Vezzoli ◽

Paolo Duminuco ◽

...

Keyword(s):

Retrospective Analysis ◽

Multiple Regression ◽

Semen Analysis ◽

Final Height ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Bone Age ◽

Testicular Development ◽

Testosterone Replacement Therapy ◽

Male Patients

Abstract CHH is a rare disease characterized by a failure to enter (complete forms) or to complete (partial forms) pubertal development. It has a strong genetic background and it needs a treatment to allow the puberty to complete. In male this goal could be achieved either by the classic testosterone replacement therapy or by the exogenous gonadotropins (Gn) administration which allows both the endogenous testosterone production and the testicular development. So far, only few studies have explored this latter therapeutic approach in inducing the CHH pubertal development and no internationally recognized protocols are available. Aim of this retrospective analysis is to (i) investigate clinical and biochemical predictors of testicular response to Gn-induced puberty in CHH; (ii) study the non-reproductive outcomes of this treatment (height, body proportions) and their determinants. A total of 19 CHH male patients, undergoing two years of Gn-mediated (FSH and hCG) puberty induction started between the ages of 14 and 23 years, were retrospectively evaluated. For each patient clinical history, physical examination, hormonal evaluation, and genetic analysis using Targeted Next Generation Sequencing for CHH genes was performed; 8 patients accepted to perform a semen analysis (SA) at the end of their treatment.Mann Whitney test and multiple regression analysis showed testicular volume after 24 months of Gn-mediated pubertal induction, to be significantly associated with: (i) the presence of cryptorchidism; (ii) the presence of a completely definable genetic cause for the disease; (iii) the presence of a complete CHH form. No significant association was found with the cumulative dose of hCG administered in 24 months. The statistical analyses regarding SA could not find the same associations. Multiple regression analyses investigating the eunuchoid habitus and a measure of the difference of subject’s final height from his target (deltaSDSth), showed a significant association with: (i) age at the beginning of the induction; (ii) the duration of growth during induction; (iii) and (for deltaSDSth) bone age before the induction. Duration of growth during induction resulted to be associated with previous testosterone priming and with partial CHH.In summary, our study confirms cryptorchidism and complete genetic forms of CHH as negative predictors of testicular response probably because they usually affect early phases of life with a complete GnRH deficiency. We also found that the eunuchoid habitus and deltaSDSth are associated not only with delayed treatment, but also with the duration of stature growth during the induction, apparently related to earlier androgenization.

Download Full-text

Congenital hypogonadotropic hypogonadism: from clinical characteristics to genetic aspects

Precision and Future Medicine ◽

10.23838/pfm.2021.00093 ◽

2021 ◽

Vol 5 (3) ◽

pp. 97-105

Author(s):

Ahreum Kwon ◽

Ho-Seong Kim

Keyword(s):

Clinical Characteristics ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Reproductive Function ◽

Delayed Puberty ◽

Activation Process ◽

Hpg Axis ◽

Congenital Hypogonadotropic Hypogonadism ◽

Sexual Characteristics ◽

Main Component

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by a deficiency in gonadotropin-releasing hormone (GnRH). CHH is characterized by delayed puberty and/or infertility; this is because GnRH is the main component of the hypothalamic-pituitary-gonadal (HPG) axis, which is a key factor in pubertal development and reproductive function completion. However, since the development of sexual characteristics and reproduction begins in the prenatal period and is very complex and delicate, the clinical characteristics and involved genes are very diverse. In particular, the HPG axis is activated three times in a lifetime, and the symptoms and biochemical findings of CHH vary by period. In addition, related genes also vary according to the formation and activation process of the HPG axis. In this review, the clinical characteristics and treatment of CHH according to HPG axis activation and different developmental periods are reviewed, and the related genes are summarized according to their pathological mechanisms.

Download Full-text

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Acta Endocrinologica ◽

10.1530/eje-10-0083 ◽

2010 ◽

Vol 162 (5) ◽

pp. 835-851 ◽

Cited By ~ 69

Author(s):

Frédéric Brioude ◽

Jérôme Bouligand ◽

Séverine Trabado ◽

Bruno Francou ◽

Sylvie Salenave ◽

...

Keyword(s):

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Genetic Alterations ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Gonadotropin Secretion ◽

Endocrine Disorder ◽

Congenital Hypogonadotropic Hypogonadism ◽

Kallmann's Syndrome ◽

Kallmann’S Syndrome

Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defectiveGNRHrelease, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormalGNRHneuron ontogenesis and is associated with anosmia or hyposmia.In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a non-endocrine disorder, other mutations affectingGNRHand/or gonadotropin secretion have been reported.Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affectingGNRHsecretion (mutations inGNRH1,GPR54/KISS1RandTAC3andTACR3) or theGNRHsensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype–phenotype relationships.

Download Full-text

GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism

Endocrine Connections ◽

10.1530/ec-17-0104 ◽

2017 ◽

Vol 6 (6) ◽

pp. 360-366 ◽

Cited By ~ 6

Author(s):

Catarina I Gonçalves ◽

José M Aragüés ◽

Margarida Bastos ◽

Luísa Barros ◽

Nuno Vicente ◽

...

Keyword(s):

Autosomal Recessive ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Autosomal Recessive Inheritance ◽

Cross Sectional Study ◽

Cross Sectional ◽

Congenital Hypogonadotropic Hypogonadism ◽

Frameshift Deletion ◽

Monoallelic Mutation ◽

Biallelic Mutations

Objective Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH) and, unlike Kallmann syndrome, is associated with a normal sense of smell. Mutations in the GNRHR gene cause autosomal recessive nCHH. The aim of this study was to determine the prevalence of GNRHR mutations in a group of 40 patients with nCHH. Design Cross-sectional study of 40 unrelated patients with nCHH. Methods Patients were screened for mutations in the GNRHR gene by DNA sequencing. Results GNRHR mutations were identified in five of 40 patients studied. Four patients had biallelic mutations (including a novel frameshift deletion p.Phe313Metfs*3, in two families) in agreement with autosomal recessive inheritance. One patient had a heterozygous GNRHR mutation associated with a heterozygous PROKR2 mutation, thus suggesting a possible role of synergistic heterozygosity in the pathogenesis of the disorder. Conclusions This study further expands the spectrum of known genetic defects associated with nCHH. Although GNRHR mutations are usually biallelic and inherited in an autosomal recessive manner, the presence of a monoallelic mutation in a patient should raise the possibility of a digenic/oligogenic cause of nCHH.

Download Full-text

Study of CHD7 gene in KAL 1-negative patients previously diagnosed with congenital hypogonadotropic hypogonadism that develop new pituitary deficiencies

Endocrine Abstracts ◽

10.1530/endoabs.49.ep904 ◽

2017 ◽

Author(s):

Beatriz Lecumberri ◽

Francisco Javier Rodriguez ◽

Oscar Moreno ◽

Manuel de Santiago ◽

Manuel Nistal ◽

...

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Congenital Hypogonadotropic Hypogonadism ◽

Chd7 Gene

Download Full-text

Immediate Post-Extraction Short Implant Placement with Immediate Loading and without Extraction of an Impacted Maxillary Canine: Two Case Reports

Materials ◽

10.3390/ma14112757 ◽

2021 ◽

Vol 14 (11) ◽

pp. 2757

Author(s):

José Antonio Moreno-Rodríguez ◽

Julia Guerrero-Gironés ◽

Francisco Javier Rodríguez-Lozano ◽

Miguel Ramón Pecci-Lloret

Keyword(s):

Dental Implant ◽

Alveolar Bone ◽

Case Reports ◽

Young Patients ◽

Aesthetic Result ◽

First Choice ◽

Surgical Extraction ◽

Impacted Canine ◽

Short Implant

For the treatment of impacted maxillary canines, traction associated with a complete orthodontic treatment is the first choice in young patients. However, in adults, this treatment has a worse prognosis. The surgical extraction of the impacted tooth can result in a series of complications and a compromised alveolar bone integrity, which may lead to the requirement of a bone regeneration/grafting procedure to replace the canine with a dental implant. These case reports aimed to describe an alternative treatment procedure to the surgical extraction of impacted maxillary canines in adults. Following clinical and computerized tomography-scan (CT-Scan) examination, the possibility of maintaining the impacted canine in its position and replacing the temporary canine present in its place with a dental implant was planned. A short dental implant with an immediate provisional crown was placed, without contacting the impacted canine. At 3 months follow-up, a definitive metal-ceramic restoration was placed. Follow-up visits were performed periodically. The implant site showed a physiological soft tissue color and firmness, no marginal bone loss, no infection or inflammation, and an adequate aesthetic result in all follow-up visits. These results suggest that the treatment carried out is a valid option to rehabilitate with an osseointegrated short implant area where a canine is included, as long as there is a sufficient amount of the remaining bone.

Download Full-text

NDNF variants are rare in patients with congenital hypogonadotropic hypogonadism

Human Genome Variation ◽

10.1038/s41439-021-00137-x ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Satoshi Tamaoka ◽

Erina Suzuki ◽

Atsushi Hattori ◽

Tsutomu Ogata ◽

Maki Fukami ◽

...

Keyword(s):

Splice Site ◽

Genetic Heterogeneity ◽

Hypogonadotropic Hypogonadism ◽

Causative Gene ◽

Synonymous Substitutions ◽

Congenital Hypogonadotropic Hypogonadism ◽

Site Recognition

AbstractAlthough NDNF was recently reported as a novel causative gene for congenital hypogonadotropic hypogonadism (CHH), this conclusion has yet to be validated. In this study, we sequenced NDNF in 61 Japanese CHH patients. No variants, except for nine synonymous substitutions that appear to have no effect on splice-site recognition, were identified in NDNF coding exons or flanking intronic sequences. These results indicate the rarity of NDNF variants in CHH patients and highlight the genetic heterogeneity of CHH.

Download Full-text