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

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.

Delayed puberty in males with β-thalassemia major: pulsatile gonadotropin-releasing hormone administration induces changes in gonadotropin isoform profiles and an increase in sex steroids

Acta Endocrinologica ◽

10.1530/eje.0.1330048 ◽

1995 ◽

Vol 133 (1) ◽

pp. 48-56 ◽

Cited By ~ 8

Author(s):

Sandra Valenti ◽

Massimo Giusti ◽

Dorothy McGuinness ◽

Roberta Guido ◽

Pier Giorgio Mori ◽

...

Keyword(s):

Sex Steroids ◽

Early Stage ◽

Thalassemia Major ◽

Delayed Puberty ◽

Gonadal Function ◽

Releasing Hormone ◽

Hormone Administration ◽

Pulsatile Gnrh

Valenti S, Giusti M, McGuinness D, Guido R, Mori PG, Giordano G, Dahl KD. Delayed puberty in males with β-thalassemia major: pulsatile gonadotropin-releasing hormone administration induces changes in gonadotropin isoform profiles and an increase in sex steroids. Eur J Endocrinol 1995;133:48–56. ISSN 0804–4643 Patients with β-thalassemia major often have pubertal delay, the etiology of which has not been fully elucidated. We investigated the pituitary–gonadal response to short-term subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administration (150 ng/kg body weight every 120 min for 7 days) in five young males (aged 13.6–19.0 years) affected by β-thalassemia major and presenting signs of delayed puberty. Immunoreactive and bioactive gonadotropin levels were determined and their isoform profiles were examined, before and after GnRH treatment, in a pool of samples collected every 15 min for 240 min. Testosterone, androstenedione, 17-hydroxyprogesterone, dehydroepian-drosterone and 17 β-estradiol were measured as markers of gonadal function on days 0, 1, 3, 5 and 7 of treatment. Five patients (aged 16.9–26.8 years) with confirmed diagnosis of idiopathic hypogonadotropic hypogonadism who were starting pulsatile GnRH therapy were also studied in the same protocol. Increased sex steroid levels were observed in both groups as a result of treatment. On day 7, the thalassemic patients had increased bioactive luteinizing hormone (LH) and follide-stimulating hormone (FSH), although immunoreactive LH and FSH were comparable to day 0. Moreover, fewer acidic and more basic immunoreactive and bioactive isoforms were noted in LH profiles on day 7. Similar results were observed in hypogonadal patients, who also had increased immunoreactive LH and FSH values. We suggest that the early stage of delayed puberty in thalassemia might be characterized by a neuroendocrine dysfunction resulting in an impaired hypothalamic GnRH release, which is inadequate for a proper pituitary stimulation. Pulsatile GnRH treatment seems to re-establish partially the correct pituitary–gonadal function. Sandra Valenti, Department of Endocrinology and Metabolism, 6 Viale Benedetto XV, 16132 Genoa, Italy

Functional Characteristics of Novel FGFR1 Mutations in Patients with Isolated Gonadotropin-Releasing Hormone Deficiency

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1151-4800 ◽

2020 ◽

Author(s):

Jin-Ho Choi ◽

Arum Oh ◽

Yena Lee ◽

Gu-Hwan Kim ◽

Han-Wook Yoo

Keyword(s):

Pubertal Development ◽

Delayed Puberty ◽

Functional Assay ◽

Functional Characteristics ◽

Releasing Hormone ◽

Phenotypic Spectrum ◽

The Impact

Abstract Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) has a wide phenotypic spectrum including Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). FGFR1 mutations have been identified in 3–10% of patients with KS or nIHH. This study was performed to investigate clinical phenotypes and functional characteristics of FGFR1 mutations in patients with IGD. Methods This study included 8 patients (from 7 families) with FGFR1 mutations identified by targeted gene panel sequencing or whole exome sequencing (WES). The impact of the identified mutations on FGFR1 function was assessed using in vitro studies. Results Seven heterozygous mutations in FGFR1 were identified in 8 patients from 7 independent families. The patients exhibited a wide spectrum of pubertal development, including anosmia in a prepubertal boy (n=1), delayed puberty (n=2), nIHH (n=3), and KS (n=2). Four of the mutations were classified as likely pathogenic, and the other three were variants of uncertain significance. FGF8-FGFR1 signaling activities for the novel FGFR1 variants (p.Y339H, p.S681I, and p.N185Kfs*16) were reduced by in vitro functional assay, indicating loss-of-function mutations. Conclusions This study identified seven rare sequence variants in FGFR1 in patients with KS and nIHH. Probands with an FGFR1 mutations displayed a wide phenotypic spectrum ranging from KS to anosmia. A prepubertal male with anosmia should be followed up to assess pubertal development because they can manifest hypogonadotropic hypogonadism after puberty. These results expand the phenotypic spectrum of FGFR1 mutations and suggest a broader biologic role of FGFR1 in reproduction.

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

Journal of Pediatrics & Neonatal Biology ◽

10.33140/jpnb.04.02.04 ◽

2019 ◽

Vol 4 (2) ◽

Keyword(s):

Environmental Factors ◽

Normal Population ◽

Pubertal Development ◽

Hormone Replacement ◽

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.

Long-Term Administration of Gonadotropin-Releasing Hormone in Men with Idiopathic Hypogonadotropic Hypogonadism

Annals of Internal Medicine ◽

10.7326/0003-4819-105-6-848 ◽

1986 ◽

Vol 105 (6) ◽

pp. 848 ◽

Cited By ~ 39

Author(s):

DANIEL I. SPRATT

Keyword(s):

Idiopathic Hypogonadotropic Hypogonadism ◽

Releasing Hormone ◽

Term Administration

Homozygous p.R31H GNRH1 mutation and normosmic congenital hypogonadotropic hypogonadism in a patient and self-limited delayed puberty in his relatives

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0207 ◽

2020 ◽

Vol 33 (9) ◽

pp. 1237-1240

Author(s):

Cécile Brachet ◽

Caroline Gernay ◽

Emese Boros ◽

Julie Soblet ◽

Catheline Vilain ◽

...

Keyword(s):

Index Case ◽

Rare Condition ◽

Delayed Puberty ◽

Case Presentation ◽

Releasing Hormone ◽

Congenital Hypogonadotropic Hypogonadism ◽

The One

AbstractObjectivesCongenital hypogonadotropic hypogonadism (CHH) is a rare condition resulting from GnRH deficiency. Gonadotropin Releasing Hormone 1 (GNRH1) homozygous mutations are an extremely rare cause of normosmic CHH (nCHH). Most heterozygous individuals are asymptomatic, with the notable exception of individuals heterozygous for a p.R31C GNRH1 mutation.Case presentationThe patient is an index case from a consanguineous family, presenting with severe CHH and his parents presenting with late puberty and normal fertility. The index case is homozygous for a p.R31H GNRH1 variant, both parents being heterozygous. The analysis of a panel of genes implicated in CHH does not show any other clinically relevant variant in any other gene tested.ConclusionsGNRH1 mutations are a rare cause of nCHH. Five different mutations have been reported so far in homozygous individuals. Most are frameshift in nature but the one reported here causes an amino acid change in the Gonadotropin-releasing hormone (GnRH) decapeptide. Both independently reported patients with the p.R31H mutation are from Turkish origin. The question of the possible role of this mutation in the late puberty of the heterozygous parents needs further documentation. An analogy is made with the heterozygous individuals carrying the p.R31C and displaying partial CHH. No nonreproductive disorder is noted.

Recent advances in the understanding and management of delayed puberty

Archives of Disease in Childhood ◽

10.1136/archdischild-2014-307963 ◽

2015 ◽

Vol 101 (5) ◽

pp. 481-488 ◽

Cited By ~ 29

Author(s):

Christina Wei ◽

Elizabeth Clare Crowne

Keyword(s):

Environmental Factors ◽

Pulse Generator ◽

Pubertal Development ◽

Hormone Replacement ◽

Sex Steroid ◽

Delayed Puberty ◽

Physiological Basis ◽

Releasing Hormone ◽

Hypogonadotrophic Hypogonadism ◽

Recent Advances

Delayed puberty, especially in boys, is a common presentation in paediatrics. Recent advances have improved our understanding of the neuroendocrine, genetic and environmental factors controlling pubertal development, and hence inform the pathophysiology of delayed puberty. The discovery of kisspeptin signalling through its receptor identified neuroendocrine mechanisms controlling the gonadotrophin-releasing hormone (GnRH) pulse generator at the onset of puberty. Genetic mechanisms from single gene mutations to single nucleotide polymorphism associated with delayed puberty are being identified. Environmental factors, including nutritional factors and endocrine disruptors, have also been implicated in changes in secular trends and abnormal timing of puberty. Despite these advances, the key clinical question is to distinguish delayed puberty associated with an underlying pathology or hypogonadism from constitutional delay in growth and puberty, which remains challenging as biochemical tests are not always discriminatory. The diagnostic accuracies of newer investigations, including 36-hour luteinising hormone releasing hormone (LHRH) tests, GnRH-agonist tests, antimullerian hormone and inhibin-B, require further evaluation. Sex hormone replacement remains the main available treatment for delayed puberty, the choice of which is largely dictated by clinical practice and availability of the various sex steroid preparations. Spontaneous reversal of hypogonadism has been reported in boys with idiopathic hypogonadotrophic hypogonadism after a period of sex steroid treatment, highlighting the importance of reassessment at the end of pubertal induction. Novel therapies with a more physiological basis such as gonadotrophins or kisspeptin-agonist are being investigated for the management of hypogonadotrophic hypogonadism. Careful clinical assessment and appreciation of the normal physiology remain the key approach to patients with delayed puberty.

Normosmic idiopathic hypogonadotropic hypogonadism due to a novel GNRH1 variant in two siblings

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-19-0145 ◽

2020 ◽

Vol 2020 ◽

Author(s):

Satyanarayana V Sagi ◽

Hareesh Joshi ◽

Emily Whiles ◽

Mondy Hikmat ◽

Vijith R Puthi ◽

...

Keyword(s):

Pituitary Gland ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Delayed Puberty ◽

List Type ◽

Idiopathic Hypogonadotropic Hypogonadism ◽

Releasing Hormone ◽

Pathogenic Variants

Summary Hypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea. Learning points: IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both. Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH. IHH is associated with a wide spectrum of clinical manifestations. IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.