scholarly journals Exogenous Kisspeptin Administration as a Probe of GnRH Neuronal Function in Patients With Idiopathic Hypogonadotropic Hypogonadism

2014 ◽  
Vol 99 (12) ◽  
pp. E2762-E2771 ◽  
Author(s):  
Yee-Ming Chan ◽  
Margaret F. Lippincott ◽  
James P. Butler ◽  
Valerie F. Sidhoum ◽  
Cindy X. Li ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Functional Capacity ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Fundamental Property ◽  
Neuronal Function ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
The Subject ◽  
Lh Secretion ◽  
Robust Response

Context: Idiopathic hypogonadotropic hypogonadism (IHH) results from defective synthesis, secretion, or action of GnRH. Kisspeptin is a potent stimulus for GnRH secretion. Objective: We probed the functional capacity of the GnRH neuronal network in patients with IHH. Participants: Eleven subjects with congenital IHH (9 men and 2 women) and one male subject who underwent reversal of IHH were studied. Six of the twelve subjects had an identified genetic cause of their IHH: KAL1 (n = 1), FGFR1 (n = 3), PROKR2 (n = 1), GNRHR (n = 1). Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 nmol/kg) and GnRH (75 ng/kg) both pre- and post-six days of treatment with exogenous GnRH (25 ng/kg sc every 2 h). Results: All subjects with abiding IHH failed to demonstrate a GnRH-induced LH response to exogenous kisspeptin. In contrast, the subject who achieved reversal of his hypogonadotropism demonstrated a robust response to kisspeptin. Conclusions: The functional capacity of the GnRH neuronal network in IHH patients is impaired, as evidenced by their inability to respond to the same dose of kisspeptin that effects a robust GnRH-induced LH response in healthy men and luteal-phase women. This impairment is observed across a range of genotypes, suggesting that it reflects a fundamental property of GnRH neuronal networks that have not been properly engaged during pubertal development. In contrast, a patient who had experienced reversal of his hypogonadotropism responded to exogenous kisspeptin.

scholarly journals Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty

2016 ◽  
Vol 101 (8) ◽  
pp. 3061-3069 ◽  
Author(s):  
Margaret F. Lippincott ◽  
Yee-Ming Chan ◽  
Angela Delaney ◽  
Dianali Rivera-Morales ◽  
James P. Butler ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Sexual Maturation ◽  
Hypogonadotropic Hypogonadism ◽  
Blood Sampling ◽  
Endocrine Activity ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Lh Pulsatility ◽  
Reproductive Endocrine ◽  
Spontaneous Activation ◽  
Lh Secretion

Context: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. Objective: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal. Participants: Six men with congenital IHH and evidence for reversal. Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24–2.4 nmol/kg) and GnRH (75 ng/kg). Results: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin. Conclusions: The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness.

Idiopathic hypogonadotropic hypogonadism: a rare cause of primary amenorrhoea in adolescence—a review and update on diagnosis, management and advances in genetic understanding.

2021 ◽  
Vol 14 (4) ◽  
pp. e239495
Author(s):  
Grace Cham ◽  
Brooke O'Brien ◽  
Rebecca MN Kimble
Keyword(s):  
Genetic Disorders ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Serum Levels ◽  
Breast Development ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Primary Amenorrhoea ◽  
Normal Menstrual Cycle ◽  
Uterine Growth

Idiopathic hypogonadotropic hypogonadism (IHH) refers to a family of genetic disorders that affect the production and/or action of gonadotropic-releasing hormone, resulting in reduced serum levels of sex steroids. This condition has a prevalence of 1–10 cases/100 000 births and is characterised by the absence of spontaneous pubertal development. In women, the condition is characterised by the onset of normal adrenarche, with the absence of thelarche and menarche. Pubertal induction for breast development and uterine growth with oestradiol, and sequential maintenance of a normal menstrual cycle and adequate oestrogen for bone health, with an oestrogen and progesterone, is considered first-line treatment. Pregnancy can be achieved in patients who have received and responded to treatment with ovulation induction with exogenous gonadotrophins. Advances in genetic testing have led to increased research and understanding of the underlying genetics of IHH with gene mutations described in up to 50% of all IHH cases.

scholarly journals Kallmann’s Syndrome: A Comparison of the Reproductive Phenotypes in Men Carrying KAL1 and FGFR1/KAL2 Mutations

2008 ◽  
Vol 93 (3) ◽  
pp. 758-763 ◽  
Author(s):  
Sylvie Salenave ◽  
Philippe Chanson ◽  
Hélène Bry ◽  
Michel Pugeat ◽  
Sylvie Cabrol ◽  
...  
Keyword(s):  
Plasma Level ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Gonadotropin Secretion ◽  
Lh Pulsatility ◽  
Kallmann's Syndrome ◽  
Severe Impairment ◽  
Basal Plasma ◽  
Kallmann’S Syndrome ◽  
Lh Secretion

Abstract Context: Kallmann’s syndrome (KS) is a genetically heterogeneous disorder consisting of congenital hypogonadotropic hypogonadism (CHH) with anosmia or hyposmia. Objective: Our objective was to compare the reproductive phenotypes of men harboring KAL1 and FGFR1/KAL2 mutations. Design and Patients: We studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 and 18 in FGFR1/KAL2, but none had additional mutations in PROK-2 or PROKR-2 genes. Results: Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete CHH. Three patients with FGFR1/KAL2 mutations had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent (14 of 21 vs. 3 of 15; P < 00.1) and testicular volume (2.4 ± 1.1 vs. 5.4 ± 2.4 ml; P < 0.001) was smaller in CHH subjects with KAL1 mutations than in subjects with FGFR1/KAL2 mutations. The mean basal plasma FSH level (0.72 ± 0.47 vs. 1.48 ± 0.62 IU/liter; P < 0.05), serum inhibin B level (19.3 ± 10.6 vs. 39.5 ± 19.3 pg/ml; P < 0.005), basal LH plasma level (0.57 ± 0.54 vs. 1.0 ± 0.6 IU/liter; P < 0.01), and GnRH-stimulated LH plasma level (1.2 ± 1.0 vs. 4.1 ± 3.5 IU/liter; P < 0.01) were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 CHH subjects with KAL1 mutations and seven subjects with FGFR1/KAL2 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. Conclusion: KAL1 mutations result in a more severe reproductive phenotype than FGFR1/KAL2 mutations. The latter are associated with a broader spectrum of pubertal development and with less severe impairment of gonadotropin secretion.

scholarly journals Ovarian Function and Reproductive Hormone Levels in Girls with Prader-Willi Syndrome: A Longitudinal Study

2012 ◽  
Vol 97 (9) ◽  
pp. E1766-E1773 ◽  
Author(s):  
Elbrich P. C. Siemensma ◽  
A. A. E. M. (Janielle) van Alfen-van der Velden ◽  
Barto J. Otten ◽  
Joop S. E. Laven ◽  
Anita C. S. Hokken-Koelega
Keyword(s):  
Ovarian Function ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Primordial Follicle ◽  
Inhibin B ◽  
Female Adolescents ◽  
Prader Willi Syndrome ◽  
Longitudinal Assessment ◽  
Reference Levels ◽  
Lh Secretion

Context: The etiology of hypogonadism in girls with Prader-Willi syndrome (PWS) remains uncertain. Objectives: The aim of the study was to evaluate gonadal function longitudinally in girls and female adolescents with PWS. Measurements: We performed a longitudinal assessment of anti-Müllerian hormone (AMH), gonadotropins, estradiol (E2), inhibin B and A, and pubertal development in girls and female adolescents with PWS. Patients and Methods: Sixty-one girls participating in the Dutch PWS Cohort study participated in the study. Serum AMH, gonadotropins, E2, and inhibin B and A levels were compared with reference values. Results: AMH levels in girls and female adolescents with PWS were comparable to reference levels between 6 months and 22 yr of age. From 10 yr of age, FSH and LH levels increased to above the 5th percentile compared to reference levels. E2 and inhibin B levels were in the low normal range in the majority, and inhibin A levels were low but detectable in almost half the female adolescents with PWS. The median age at puberty onset was comparable, but the median ages at attaining Tanner M3 (P = 0.05) and M4 (P < 0.0001) were significantly higher in girls with PWS than in healthy references. Conclusion: Our study shows that the primordial follicle pool and number of small antral follicles are conserved in girls and female adolescents with PWS. We found no classical hypogonadotropic hypogonadism. However, maturation of follicles and progression of pubertal development are impaired, which might be due to dysregulation of LH secretion. Because these impairments are not absolute, ovulation and thus conception cannot be ruled out in individual female adolescents with PWS.

scholarly journals Parallel Multi-Gene Panel Testing for Diagnosis of Idiopathic Hypogonadotropic Hypogonadism/Kallmann Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-3 ◽  
Author(s):  
Manickavasagam Senthilraja ◽  
Aaron Chapla ◽  
Felix K. Jebasingh ◽  
Dukhabhandhu Naik ◽  
Thomas V. Paul ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Cost Effective ◽  
Kallmann Syndrome ◽  
Causative Gene ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Panel Testing ◽  
Kal1 Gene ◽  
Gene Panel Testing ◽  
The Subject

Kallmann syndrome (KS)/Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by hypogonadotropic hypogonadism and anosmia or hyposmia due to the abnormal migration of olfactory and gonadotropin releasing hormone producing neurons. Multiple genes have been implicated in KS/IHH. Sequential testing of these genes utilising Sanger sequencing is time consuming and not cost effective. The introduction of parallel multigene panel sequencing of small gene panels for the identification of causative gene variants has been shown to be a robust tool in the clinical setting. Utilizing multiplex PCR for the four gene KS/IHH panel followed by NGS, we describe herewith two cases of hypogonadotropic hypogonadism with a Prokineticin receptor 2 (PROKR2) gene and KAL1 gene mutation. The subject with a PROKR2 mutation had a normal perception of smell and normal olfactory bulbs on imaging. The subject with a KAL1 gene mutation had anosmia and a hypoplastic olfactory bulb.

scholarly journals Frequency of Impaired Fibroblast Growth Factor Receptor 1 Signaling as a Cause of Normosmic Idiopathic Hypogonadotropic Hypogonadism

2009 ◽  
Vol 23 (12) ◽  
pp. 2120-2121
Author(s):  
Taneli Raivio ◽  
Yisrael Sidis ◽  
Lacey Plummer ◽  
Huaibin Chen ◽  
Jinghong Ma ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Growth Factor Receptor ◽  
Cell Surface Expression ◽  
Heterozygous Mutation ◽  
Loss Of Function ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
The Impact

ABSTRACT Context FGFR1 mutations have been identified in about 10% of patients with Kallmann syndrome. Recently cases of idiopathic hypogonadotropic hypogonadism (IHH) with a normal sense of smell (nIHH) have been reported. Aims The objective of the study was to define the frequency of FGFR1 mutations in a large cohort of nIHH, delineate the spectrum of reproductive phenotypes, assess functionality of the FGFR1 mutant alleles in vitro, and investigate genotype-phenotype relationships. Design FGFR1 sequencing of 134 well-characterized nIHH patients (112 men and 22 women) and 270 healthy controls was performed. The impact of the identified mutations on FGFR1 function was assessed using structural prediction and in vitro studies. Results Nine nIHH subjects (five males and four females; 7%) harbor a heterozygous mutation in FGFR1 and exhibit a wide spectrum of pubertal development, ranging from absent puberty to reversal of IHH in both sexes. All mutations impair receptor function. The Y99C, Y228D, and I239T mutants impair the tertiary folding, resulting in incomplete glycosylation and reduced cell surface expression. The R250Q mutant reduces receptor affinity for FGF. The K618N, A671P, and Q680X mutants impair tyrosine kinase activity. However, the degree of functional impairment of the mutant receptors did not always correlate with the reproductive phenotype, and variable expressivity of the disease was noted within family members carrying the same FGFR1 mutation. These discrepancies were partially explained by additional mutations in known IHH loci. Conclusions Loss-of-function mutations in FGFR1 underlie 7% of nIHH with different degrees of impairment in vitro. These mutations act in concert with other gene defects in several cases, consistent with oligogenicity.

scholarly journals Inactivating NHLH2 Variants Cause Idiopathic Hypogonadotropic Hypogonadism and Obesity in Humans

2022 ◽  
Author(s):  
A. Kemal Topaloglu ◽  
Enver Simsek ◽  
Matthew A. Kocher ◽  
Jamala Mammadova ◽  
Ece Bober ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Late Onset ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Critical Role ◽  
Whole Body ◽  
Luciferase Reporter ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Helix Loop Helix

Abstract Metabolism has a role in determining the time of pubertal development and fertility. Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate (ARC) nucleus of the hypothalamus constitute the GnRH (Gonadotrophin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 (Nhlh2; N2KO), a class II member of the basic helix-loop-helix (bHLH) family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism (IHH) cohort revealed obese patients with rare sequence variants in NHLH2, which were characterized by in silico protein analysis, chromatin immunoprecipitation, and luciferase reporter assays. In vitro heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support NHLH2’s critical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans.

scholarly journals Uncovering Novel Reproductive Defects in Neurokinin B Receptor Null Mice: Closing the Gap Between Mice and Men

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1498-1508 ◽  
Author(s):  
Jasmine J. Yang ◽  
Claudia S. Caligioni ◽  
Yee-Ming Chan ◽  
Stephanie B. Seminara
Keyword(s):  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Corpora Lutea ◽  
Wild Type ◽  
Neurokinin B ◽  
Gnrh Release ◽  
Estrous Cyclicity ◽  
Closing The Gap ◽  
Deficient Mice ◽  
Robust Response

Patients bearing mutations in TAC3 and TACR3 (which encode neurokinin B and its receptor, respectively) have sexual infantilism and infertility due to GnRH deficiency. In contrast, Tacr3−/− mice have previously been reported to be fertile. Because of this apparent phenotypic discordance between mice and men bearing disabling mutations in Tacr3/TACR3, Tacr3 null mice were phenotyped with close attention to pubertal development, estrous cyclicity, and fertility. Tacr3−/− mice demonstrated normal timing of preputial separation and day of first estrus, markers of sexual maturation. However, at postnatal d 60, Tacr3−/− males had significantly smaller testes and lower FSH levels than their wild-type littermates. Tacr3−/− females had lower uterine weights and abnormal estrous cyclicity. Approximately half of Tacr3−/− females had no detectable corpora lutea on ovarian histology at postnatal d 60. Despite this apparent ovulatory defect, all Tacr3−/− females achieved fertility when mated. However, Tacr3−/− females were subfertile, having both reduced numbers of litters and pups per litter. The subfertility of these animals was not due to a primary ovarian defect, because they demonstrated a robust response to exogenous gonadotropins. Thus, although capable of fertility, Tacr3-deficient mice have central reproductive defects. The remarkable ability of acyclic female Tacr3 null mice to achieve fertility is reminiscent of the reversal of hypogonadotropic hypogonadism seen in a high proportion of human patients bearing mutations in TACR3. Tacr3 mice are a useful model to examine the mechanisms by which neurokinin B signaling modulates GnRH release.

A case of idiopathic hypogonadotropic hypogonadism which attained remission by LH and FSH treatment

2013 ◽  
Author(s):  
Yui Watanabe ◽  
Takeshi Hayashi ◽  
Hiroyuki Yamazaki ◽  
Katsuyoshi Tojo ◽  
Kazunori Utsunomiya
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Idiopathic Hypogonadotropic Hypogonadism
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