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 Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism

2012 ◽  
Vol 4 (3) ◽  
pp. 121-126 ◽  
Author(s):  
Fatih Gürbüz ◽  
L. Damla Kotan ◽  
Eda Mengen ◽  
Zeynep Şıklar ◽  
Merih Berberoğlu ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Idiopathic Hypogonadotropic Hypogonadism

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 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 Clinical characteristics of 138 Chinese female patients with idiopathic hypogonadotropic hypogonadism

2017 ◽  
Vol 6 (8) ◽  
pp. 800-810 ◽  
Author(s):  
Rui-yi Tang ◽  
Rong Chen ◽  
Miao Ma ◽  
Shou-qing Lin ◽  
Yi-wen Zhang ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Chinese Women ◽  
Hypogonadotropic Hypogonadism ◽  
Live Birth Rate ◽  
Bone Age ◽  
Hormone Treatment ◽  
Academic Medical Centre ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Primary Amenorrhoea ◽  
Magnetic Resonance Imaging Mri

Objective To evaluate the clinical features of Chinese women with idiopathic hypogonadotropic hypogonadism (IHH). Methods We retrospectively reviewed the clinical characteristics, laboratory and imaging findings, therapeutic management and fertility outcomes of 138 women with IHH. All patients had been treated and followed up at an academic medical centre during 1990–2016. Results Among the 138 patients, 82 patients (59.4%) were diagnosed with normosmic IHH and 56 patients (40.6%) were diagnosed with Kallmann syndrome (KS). The patients with IHH experienced occasional menses (4.3%), spontaneous thelarche (45.7%) or spontaneous pubarche (50.7%). Women with thelarche had a higher percentage of pubarche (P < 0.001) and higher gonadotropin concentrations (P < 0.01). Olfactory bulb/sulci abnormalities were found during the magnetic resonance imaging (MRI) of all patients with KS. Most patients with IHH had osteopenia and low bone age. Among the 16 women who received gonadotropin-releasing hormone treatment, ovulation induction or assisted reproductive technology, the clinical pregnancy rate was 81.3% and the live birth rate was 68.8%. Conclusions The present study revealed that the phenotypic spectrum of women with IHH is broader than typical primary amenorrhoea with no secondary sexual development, including occasional menses, spontaneous thelarche or pubarche. MRI of the olfactory system can facilitate the diagnosis of KS. Pregnancy can be achieved after receiving appropriate treatment.

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 Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism

Endocrines ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 1-15
Author(s):  
Ali Kemal Topaloglu ◽  
Ihsan Turan
Keyword(s):  
Developmental Disorders ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Clinical Diagnostics ◽  
Sex Steroid ◽  
Genetic Etiology ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Sex Steroid Hormone ◽  
Sense Of Smell ◽  
The Face

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.

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 use of recombinant FSH in combination therapy in a young male with idiopathic hypogonadotropic hypogonadism

2018 ◽  
pp. 260-264
Author(s):  
Yu. L. Skorodok ◽  
I. Yu. Ioffe ◽  
I. I. Nagornaya ◽  
I. L. Nikitina
Keyword(s):  
Combination Therapy ◽  
Hypogonadotropic Hypogonadism ◽  
Young Male ◽  
Serum Levels ◽  
Inhibin B ◽  
Mature Stage ◽  
Recombinant Fsh ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Clinical Measurements ◽  
Spermatogenic Epithelium

Currently, testosterone drugs are used to treat hypogonadotropic hypogonadism, which allow men to get a good height and reach a stage of sexual development corresponding to their age. In this case, the testicular volume remains of pre-pubertal size, and the spermatogenic epithelium fails to reach its mature stage under such conditions. The study was aimed at initiating puberty in a 17-year-old male with hypogonadotropic hypogonadism using gonadotropic hormone drugs. The patient received foliotropinalpha injections in combination with chorionic gonadotropin for 9 months. The treatment efficacy was evaluated after 3, 6, 9 months of therapy by measuring the testicle volume (using Prader orchidometer and ultrasound) and the sex hormones and inhibin B serum levels. During the treatment period, the testicle volume increased from 1.5 to 8 ml based on clinical measurements, and from 1.38 and 1.14 to 5.8 and 5.87 ml (right and left, respectively) based on ultrasound imaging. The level of testosterone reached normal values, inhibin B also increased. The use of recombinant FSH for nine months in the combination therapy of idiopathic hypogonadotropic hypogonadism in a 17-year-old male contributed to the initiation of a true puberty.

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