Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by<i>GNRHR</i>mutations and women with polycystic ovary syndrome

Maione, Luigi; Fèvre, Anne; Nettore, Immacolata Cristina; Manilall, Ashmeetha; Francou, Bruno; Trabado, Séverine; Bouligand, Jérôme; Guiochon‐Mantel, Anne; Delemer, Brigitte; Flanagan, Colleen A.; Macchia, Paolo Emidio; Millar, Robert P.; Young, Jacques

doi:10.1093/humrep/dey339

Cited by 11 publications

(7 citation statements)

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“…A GnRH stimulation test (100 μg via i.v. bolus) failed to elicit a rise in either LH or FSH over 2-h of sampling, consistent with severe GnRH deficiency [3,29] (Fig. 4c, d).…”

Section: Evidence Of Severe Gnrh Deficiencysupporting

confidence: 61%

“…Details of the specific imaging protocol have been previously published [27]. Hormonal Assays Total testosterone was measured using a sensitive and specific radioimmunoassay (Spectra, Orion Diagnostica, Espoo, Finland) as previously reported [28,29]. The limit of detection is 0.02 ng/ mL (0.069 nmol/L).…”

Section: Methodsmentioning

confidence: 99%

“…Variants were reported in agreement with Human Genome Variation Society nomenclature. Variants identified by both exome procedures were analyzed in silico by previously published prediction programs (PolyPhen Mutation Taster and Panther, Mutation Taster, Sorting Intolerant From Tolerant) and [26,29,36,37] Alamut as previously reported [29]. Identified variants were classified according to American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology [38].…”

Section: Genetic Analysesmentioning

confidence: 99%

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Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

et al. 2020

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Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

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“…A GnRH stimulation test (100 μg via i.v. bolus) failed to elicit a rise in either LH or FSH over 2-h of sampling, consistent with severe GnRH deficiency [3,29] (Fig. 4c, d).…”

Section: Evidence Of Severe Gnrh Deficiencysupporting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Section: Genetic Analysesmentioning

confidence: 99%

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Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

et al. 2020

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“…CHH may manifest as partial hypogonadism, leading to a variable degree of pubertal development in females carrying mutations in autosomal genes, for example, fibroblast growth factor 1 (FGF1), prokineticin 2 (PROK2) / prokineticin 2 receptor (PROKR2), and GnRH receptor (GNRHR) (34,35,36,37). Biallelic, partial loss-offunction mutations in GNRHR cause a wide spectrum of reproductive phenotypes from CDGP to complete CHH (33,38). In a series of twelve patients, ten (83%) had primary amenorrhea, eight had partial, three complete, and one no breast development (38).…”

Section: Figurementioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary amenorrhea and female delayed puberty

Seppä

Kuiri-Hänninen

Holopainen

et al. 2021

European Journal of Endocrinology

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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.

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“…Клинические проявления нарушения работы репродуктивной оси при этом состоянии сходны с проявлениями ЦГ: ановуляция, олиго-и аменорея. Более того, у пациенток с ЦГ при ультразвуковом исследовании органов малого таза могут быть выявлены ультразвуковые признаки СПКЯ со стороны яичников -увеличение их объема и количества фолликулов [18,19]. Отсутствие же гиперандрогенемии -как клинической, так и биохимической -у пациенток с ановуляторным бесплодием исключает СПКЯ и может указывать на наличие у них ЦГ.…”

Section: Discussionunclassified

Basal level of luteinizing hormone as a key marker of the idiopathic central hypogonadism in women

Loktionova

Ilovayskaya

2020

Alʹm. klin. med.

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Background: Central hypogonadism (CH) is a syndrome characterized by low levels of peripheral sex steroid hormones due to the lack of central (hypothalamic-pituitary) regulation of reproductive system. In females, CH clinically manifests by amenorrhea, anovulation, and infertility. The classical diagnostic criteria of CH in the absence of organic disease of hypothalamic-pituitary region (“idiopathic” CH) include low gonadotropin levels; however, their levels within the reference ranges do not exclude CH. Moreover, reference ranges for these parameters are different between laboratories. Thus, currently no clear laboratory diagnostic criteria for female CH are available.Aim: To determine the diagnostic value of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) basal levels for the confirmation of CH diagnosis in women and to identify cutoffs of basal gonadotropins levels, which can be considered as diagnostic criteria for female CH.Materials and methods: This cross-sectional study included 87 women: 49 with confirmed CH, aged 18 to 36 years (median, 24 [Q21; Q29]), and 38 healthy fertile women with regular menstrual cycles aged 21 to 45 years (median, 23 [Q23; Q28]). In all subjects, LH, FSH, estradiol, testosterone, prolactin, and free thyroxin levels were measured by chemiluminiscent immunoassay.Results: LH, FSH, estradiol, and prolactin levels in the CH patients were significantly lower than those in healthy subjects. The ROC analysis showed that LH level ≤ 1.95 ME/l indicated the central genesis of hypogonadism with sensitivity of 81.25% and specificity of 91.89%. Basal FSH level ≤ 5.075 ME/l had a 70.00% sensitivity and 77.14% specificity for CH diagnosis.Conclusion: Basal LH level ≤ 1.95 ME/l measured by chemiluminiscent immunoassay can be considered as an idiopathic CH diagnostic criterion in female with amenorrhea due to the hypoestrogenemia with sensitivity of > 80% and specificity > 90%.

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Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused byGNRHRmutations and women with polycystic ovary syndrome

Cited by 11 publications

References 40 publications

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary amenorrhea and female delayed puberty

Basal level of luteinizing hormone as a key marker of the idiopathic central hypogonadism in women

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