scholarly journals Congenital hypogonadotropic hypogonadism: from clinical characteristics to genetic aspects

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.

scholarly journals Diagnosis and management of of primary amenorrhea and female delayed puberty

2021 ◽  
Author(s):  
Satu Seppä ◽  
Tanja Kuiri-Hänninen ◽  
Elina Holopainen ◽  
Raimo Voutilainen
Keyword(s):  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Reproductive Capacity ◽  
Breast Development ◽  
Delayed Puberty ◽  
Primary Amenorrhea ◽  
Secondary Sexual Characteristics ◽  
Sexual Characteristics ◽  
Old Females ◽  
Secondary Sexual

Puberty is the period of transition from childhood to adulthood characterized by the attainment of adult height and body composition, accrual of bone strength and the acquisition of secondary sexual characteristics, psychosocial maturation and reproductive capacity. In girls, menarche is a late marker of puberty. Primary amenorrhea is defined as the absence of menarche in ≥15-year-old females with developed secondary sexual characteristics and normal growth or that in ≥13-year-old females without signs of pubertal development. Furthermore, evaluation for primary amenorrhea should be considered in the absence of menarche three years after thelarche (start of breast development) or five years after thelarce, if that occurred before the age of 10 years. A variety of disorders in the hypothalamus-pituitary-ovarian axis can lead to primary amenorrhea with delayed, arrested or normal pubertal development. Etiologies can be categorized as hypothalamic or pituitary disorders causing hypogonadotropic hypogonadism, gonadal disorders causing hypergonadotropic hypogonadism, disorders of other endocrine glands, and congenital utero-vaginal anomalies. This article gives a comprehensive review of the etiologies, diagnostics and management of primary amenorrhea from the perspective of pediatric endocrinologists and gynecologists. The goals of treatment vary depending on both the etiology and patient; with timely etiological diagnostics fertility may be attained even in those situations where no curable treatment exists.

scholarly journals The human chorionic gonadotropin test is more powerful than the gonadotropin-releasing hormone agonist test to discriminate male isolated hypogonadotropic hypogonadism from constitutional delayed puberty

2003 ◽  
pp. 23-29 ◽  
Author(s):  
V Degros ◽  
C Cortet-Rudelli ◽  
B Soudan ◽  
D Dewailly
Keyword(s):  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Testosterone Level ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Serum Testosterone ◽  
Serum Testosterone Level ◽  
Delayed Puberty ◽  
Hcg Test

OBJECTIVE: The effectiveness of biological investigations aiming at discriminating isolated hypogonadotropic hypogonadism (IHH) from constitutional delayed puberty (CDP) in male patients is still controversial. We revisited the diagnostic power of the basal serum testosterone level, the Triptorelin test and the human chorionic gonadotropin (hCG) test in a cohort of 33 boys with delayed puberty. DESIGN: Boys were aged 14.2 to 26.2 Years at referral. A 5-Year-long clinical follow-up after the initial study allowed confirmation of the diagnosis. At the end of the follow-up period, IHH was found in 13 patients while the other 20 had normal spontaneous pubertal development (CDP). RESULTS: At referral, a basal morning testosterone level >1.7 nmol/l was observed in 55% of patients with CDP exclusively (predictive positive value (PPV)=100%; predictive negative value (PNV)=59%). For CDP, the PPV of the LH peak 3 h after Triptorelin was 100% by setting the upper threshold at 14 IU/l and the PNV was 72%. However, no lower threshold could discriminate IHH from CDP in the remaining patients with an LH peak 3 h after Triptorelin <14 IU/l. In CDP patients, the PPV of the serum testosterone increment after hCG stimulation (deltaT/hCG) was 100% for values >9 nmol/l (PNV=72%). In IHH patients, the PPV of deltaT/hCG was 100% for values <3 nmol/l (PNV=82%). Only 29% of the studied population had a deltaT/hCG between these lower and upper thresholds and therefore could not have been classified initially. CONCLUSIONS: (i) Dynamic testing for the diagnosis of delayed puberty is useful only when the basal testosterone level is lower than 1.7 nmol/l; (ii) in that case, the hCG test has better discriminating power than the Triptorelin test and appears as the best cost-effective investigation. It prevents useless and expensive investigations in about one-half of CDP patients with a basal morning testosterone level lower than 1.7 nmol/l.

scholarly journals Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism--diagnostic and therapeutic aspects

2004 ◽  
pp. U89-U94 ◽  
Author(s):  
HA Delemarre-van de Waal
Keyword(s):  
Pulse Generator ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Gonadotropin Releasing Hormone ◽  
Delayed Puberty ◽  
Releasing Hormone ◽  
Testicular Growth ◽  
Pulsatile Gnrh ◽  
Portable Pump

BACKGROUND: Puberty is the result of reactivation of the gonadotropin releasing hormone (GnRH) pulse generator resulting in an increasing release of GnRH by the hypothalamus, which stimulates the gonadotropic cells of the pituitary to synthesize and secrete LH and FSH. Hypogonadotropic hypogonadism (HH) is often the result of GnRH deficiency. The clinical picture is characterized by the absence of pubertal development and infertility. It is difficult to differentiate HH from delayed puberty since low gonadotropin and low testosterone levels are found in both conditions. We hypothesized that long-term GnRH administration may differentiate between the two conditions by a difference in the increase of gonadotropins, the idea being that in normal delayed puberty the pituitary of the patient has been primed with GnRH during the fetal and early postnatal period. PATIENTS: Seventeen adolescents suspected of having hypogonadotropic hypogonadism were treated with pulsatile GnRH for 7 days. At the present time, the diagnosis of these patients is known and the results of the long-term GnRH stimulation have been evaluated according to the present diagnosis. RESULTS: The results show that the increase in gonadotropins following GnRH treatment is similar in both conditions. Therefore, at a prepubertal age a normal delayed puberty cannot be distinguished from hypogonadotropic hypogonadism using long-term GnRH stimulation. Long-term pulsatile GnRH treatment is a physiological therapy for the induction of puberty. Unlike testosterone it has the advantage of stimulation of testicular growth and fertility, as well as virilization, in males. We have treated 68 male patients with HH with pulsatile GnRH. The results show testicular growth and virilization in all the patients and spermatogenesis in 58 patients. Wearing a portable pump is cumbersome. However, the patients were very motivated and adapted very easily to this inconvenience. When spermatogenesis had developed, GnRH treatment was changed to human chorionic gonadotropin (hCG) administration 1-2 times per week intramuscularly or subcutaneously. During hCG therapy spermatogenesis was maintained or even improved. At least ten patients fathered children. CONCLUSION: Pulsatile GnRH cannot distinguish between a normal delayed puberty and a hypothalamic defect in still prepubertal patients. Pulsatile GnRH offers an appropriate way to initiate testicular growth including virilization and fertility in males with hypogonadotropic hypogonadism.

scholarly journals An Update on Aetiopathology, Various Genetic Causes and Management of Delayed Puberty-A Minireview

2019 ◽  
Vol 4 (2) ◽  
Keyword(s):  
Environmental Factors ◽  
Normal Population ◽  
Pubertal Development ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Clinical Signs ◽  
Sex Steroid ◽  
Delayed Puberty ◽  
Main Question ◽  
Releasing Hormone

Delayed Puberty (DP), especially in boys, is a common presentation in paediatrics. By definition DP is defined as the presentation of clinical signs of puberty 2-2.5SD later than in the normal population. With the recent advances in understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development it has become easier to understand the pathophysiology of DP. The discovery of kisspeptin signaling through its receptor identified neuroendocrine mechanisms controlling the gonadotropin releasing hormone (GnRH) pulse generator at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphisms associated with DP are being identified. Environmental factors, including nutritional factors, besides endocrine disruptors, have been associated with the secular trends and abnormal timing of puberty. Inspite of these advances, the main question remains how to differentiate DP associated with underlying pathology of hypogonadism from constitutional delay in growth and puberty (CDP) that remains challenging as biochemical tests do not always discriminate the 2.The diagnostic accuracies of newer investigations which include the 36-hour luteininzing hormone releasing hormone(LHRH) tests, GnRH agonist tests, antimullerian hormone and inhibin B, need further evaluation. Sex hormone replacement remains the main therapy that is available for DP, whose choice is based on clinical practice and the availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism has been reported in boys having idiopathic hypogonadotropic hypogonadism following sex steroid treatment, which highlights the importance of reassessment at the end of pubertal induction .Novel therapies having a more physiological bases like gonadotropins or kisspeptin agonists are getting investigated for the management of hypogonadotropic hypogonadism. A careful assessment and knowledge of the normal physiology remains the mainstay of managing patients with DP.

scholarly journals The Clinical and Genetic Characteristics of Chinese Male Pediatric Patients With Congenital Hypogonadotropic Hypogonadism

2021 ◽  
Author(s):  
Yi Wang ◽  
Miao Qin ◽  
Lijun Fan ◽  
Beibei Zhang ◽  
Chunxiu Gong
Keyword(s):  
Autosomal Recessive ◽  
Hypogonadotropic Hypogonadism ◽  
Positive Family History ◽  
Delayed Puberty ◽  
Genetic Characteristics ◽  
Cell Dysfunction ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Pathogenic Genes ◽  
Rare Phenotype ◽  
Chinese Male

Abstract BackgroundsCongenital hypogonadotropic hypogonadism (CHH) are invided into Kallmann Syndrome (KS) and normosmic HH(nHH). The clinical and genetic characteristics of CHH are more studied in adults, but less in pre-adults. MethodsMedical records of 126 patients with CHH at our hospital during 2008−2020 were evaluated. ResultsTotally, seven patients (5.6%) had hypospadias. Among 49 patients with positive family history, delayed puberty, KS/nHH and olfactory abnormalities accounted for 44.9%, 16.3%, and 12.2%, respectively. Sixty-five patients completed the hCG prolongation test, and T levels of 24 patients were lower than 100 ng/dl. 25 CHH-related genes were found in 78 patients, digenic mutations in 23 patients, and trigenic mutations in 3 patients. The most common pathogenic genes were FGFR1 (21.1%), PROKR2 ( 17.9%), ANOS1 (12.6%), and CHD7 (12.6%). The oligogenicity rate of common autosomal dominant heredity genes accounted for 50.0% (FGFR1, 10/20) and 33.3% (CHD7, 4/12), of autosomal recessive heredity gene PROKR2 accounted for 47.1% (8/17). ConclusionMicropenis and cryptorchidism are important cues for CHH in pre-adulthood; hypospadias is a rare phenotype of CHH. At least 22.9% of patients tested had testicular Leydig cell dysfunction (dual CHH). Oligogenic mutations were found in 27.4% of all patients with CHH.

scholarly journals Deletion of the Homeodomain Protein Six6 From GnRH Neurons Decreases GnRH Gene Expression, Resulting in Infertility

Endocrinology ◽  
2019 ◽  
Vol 160 (9) ◽  
pp. 2151-2164 ◽  
Author(s):  
Erica C Pandolfi ◽  
Karen J Tonsfeldt ◽  
Hanne M Hoffmann ◽  
Pamela L Mellon
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Neuronal Cell ◽  
Delayed Puberty ◽  
Homeodomain Protein ◽  
Gnrh Neuron ◽  
Direct Role ◽  
Hpg Axis ◽  
Gnrh Neurons

Abstract Hypothalamic GnRH (luteinizing hormone–releasing hormone) neurons are crucial for the hypothalamic-pituitary-gonadal (HPG) axis, which regulates mammalian fertility. Insufficient GnRH disrupts the HPG axis and is often associated with the genetic condition idiopathic hypogonadotropic hypogonadism (IHH). The homeodomain protein sine oculis–related homeobox 6 (Six6) is required for the development of GnRH neurons. Although it is known that Six6 is specifically expressed within a more mature GnRH neuronal cell line and that overexpression of Six6 induces GnRH transcription in these cells, the direct role of Six6 within the GnRH neuron in vivo is unknown. Here we find that global Six6 knockout (KO) embryos show apoptosis of GnRH neurons beginning at embryonic day 14.5 with 90% loss of GnRH neurons by postnatal day 1. We sought to determine whether the hypogonadism and infertility reported in the Six6KO mice are generated via actions within the GnRH neuron in vivo by creating a Six6-flox mouse and crossing it with the LHRHcre mouse. Loss of Six6 specifically within the GnRH neuron abolished GnRH expression in ∼0% of GnRH neurons. We further demonstrated that deletion of Six6 only within the GnRH neuron leads to infertility, hypogonadism, hypogonadotropism, and delayed puberty. We conclude that Six6 plays distinct roles in maintaining fertility in the GnRH neuron vs in the migratory environment of the GnRH neuron by maintaining expression of GnRH and survival of GnRH neurons, respectively. These results increase knowledge of the role of Six6 in the brain and may offer insight into the mechanism of IHH.

scholarly journals Hormonal changes throughout puberty in congenital hypogonadotropic hypogonadism and Pump indication

2020 ◽  
Author(s):  
Xiaoya Ren ◽  
Yuanyuan Tian ◽  
Guoshuang Feng ◽  
Yi Wang ◽  
Beibei Zhang ◽  
...  
Keyword(s):  
Operating Characteristic ◽  
Hypogonadotropic Hypogonadism ◽  
Hormonal Changes ◽  
Normal Children ◽  
Pump Therapy ◽  
Hpg Axis ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Testis Volume ◽  
Lhrh Therapy ◽  
Time Point

Abstract Background It is difficult to capture the exact time of pubertal initiation in normal children, including the detailed patterns of physical development, the cut-off values of hormone changing at pubertal initiation and maturation. Method Patients diagnosed with CHH were included in to prospectively investigate the hormones changes by GnRH pulsed pump therapy. We investigate testis volume and the hormones of HPG axis at basal and LHRH stimulated at 0 and the end of week 1, 4, and 12. Receiver operating characteristic (ROC) curve was plotted to determine the cut-off values of pubertal hormones.Results: Twenty-four CHH patients received pulse LHRH therapy were rolled in this study. ①stimulated FSH reached peak and LH increased significantly at week4. At this time point we workup the cut-off hormones values for pubertal initiation by ROC. They are: basal LH 1.32 IU/L, LH/FSH 0.34, the stimulated LH 4.45 IU/L and LH/FSH 0.54 for initiation. ②Basal INH-b elevated at week1, followed by T at week4, then AMH decreased at week12 coupled with testicle and penis growth. ③the pituitary response of CHH is normal when LH in the range of 1.81-3.17 IU/L and the LH / FSH in the range of 0.57-0.87. Conclusion ① we got the cut-off values of puberty initiation: basal LH 1.32 IU/L, stimulated LH 4.45 and LH/FSH 0.54 signed HPG axis activated. ②we got the cut-off hormones values of normal pituitary response: stimulated LH in the range of 1.81-3.17 IU/L and LH / FSH in the range of 0.57-0.87.

Disorders of male reproduction and male hypogonadism

2020 ◽  
pp. 2386-2406
Author(s):  
P.-M.G. Bouloux
Keyword(s):  
Genital Tract ◽  
Age Of Onset ◽  
Hypogonadotropic Hypogonadism ◽  
Male Reproduction ◽  
Reproductive Age ◽  
Delayed Puberty ◽  
Obstructive Azoospermia ◽  
Male Hypogonadism ◽  
Genital Tract Infection ◽  
Sexual Characteristics

The adult testis performs two principle functions: the synthesis and secretion of androgens, and the production of male germ cells, the spermatozoa. Testosterone is essential for male sexual differentiation, growth, and function of the male genital tract, secondary sexual characteristics, sexual potency, and production of spermatozoa. Hypogonadism may be due to disorders of the pituitary/hypothalamus (secondary or hypogonadotropic hypogonadism) or testes (primary or hypergonadotropic hypogonadism). Its symptoms and signs depend on the age of onset of androgen deficiency. Prepubertal presentation is with sexual infantilism, delayed puberty, and eunuchoidal body proportions. Male infertility may affect 5% of men of reproductive age and is caused by a heterogeneous group of disorders. The commonest cause (60% of cases) is ‘idiopathic’ azoo/oligozoospermia, although many cases are now recognized as due to discrete gene defects associated with impaired spermatogenesis. Other causes include cryptorchidism, testicular tumours, genital tract infection, obstructive azoospermia, and sperm autoimmunity.

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

2018 ◽  
Vol 178 (3) ◽  
pp. R55-R80 ◽  
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.

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

2010 ◽  
Vol 162 (5) ◽  
pp. 835-851 ◽  
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.

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