The Role of Prior Pubertal Development, Biochemical Markers of Testicular Maturation, and Genetics in Elucidating the Phenotypic Heterogeneity of Idiopathic Hypogonadotropic Hypogonadism

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.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-2233 ◽

2014 ◽

Vol 99 (12) ◽

pp. E2762-E2771 ◽

Cited By ~ 15

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.

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

Molecular Endocrinology ◽

10.1210/mend.23.12.9994 ◽

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.

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Inactivating NHLH2 Variants Cause Idiopathic Hypogonadotropic Hypogonadism and Obesity in Humans

10.21203/rs.3.rs-1256866/v1 ◽

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.

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