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info:eu-repo/grantAgreement/AEI/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/BFU2017-83934-P/ES/KISSPEPTINAS Y PUBERTAD - NUEVOS ASPECTOS FISIOLOGICOS E IMPLICACIONES FISIOPATOLOGICAS EN ALTERACIONES PUBERALES ASOCIADAS A OBESIDAD

The vitamin D receptor (VDR) mediates vitamin D actions beyond bone health. While VDR activation by 1,25-dihydroxyvitamin D (1,25D) leads to robust transcriptional regulation, less is known about VDR actions in the absence of 1,25D. We analyzed the transcriptomic response to 1,25D in fibroblasts bearing a severe homozygous hereditary vitamin D resistant rickets-related p.Arg30* VDR mutation (MUT) and in control fibroblasts (CO). Roughly 4.5% of the transcriptome was regulated by 1,25D in CO fibroblasts, while MUT cells without a functional VDR were insensitive to 1,25D. Novel VDR target genes identified in human fibroblasts included bone and cartilage factors CILP, EFNB2, and GALNT12. Vehicle-treated CO and MUT fibroblasts had strikingly different transcriptomes, suggesting basal VDR activity. Indeed, oppositional transcriptional effects in basal conditions versus after 1,25D activation were implied for a subset of target genes mostly involved with cell cycle. Cell proliferation assays corroborated this conjectured oppositional basal VDR activity, indicating that precise 1,25D dosage in target tissues might be essential for modulating vitamin D actions in human health.

In normal males, luteinizing hormone (LH) regulates the function of Leydig cells and, hence, male sexual differentiation, pubertal androgenization, male sexual function, and fertility. Abnormalities in the function of Leydig cells result in primary hypogonadism and varying degrees of male pseudohermaphroditism. 1-5 In these patients, Leydig cells are absent, hypoplastic, or unresponsive to stimulation with human chorionic gonadotropin (hCG), and studies of testicular-biopsy samples from some patients have revealed the absence of LH receptors. 2,3 In normal women, LH stimulates the theca cells to produce androgen precursors for aromatization to estradiol by granulosa cells during the follicular phase of the menstrual cycle. . . .

The objective of the study was to determine the stress levels of girls with central precocious puberty (CPP) before and during treatment with a long-acting gonadotropin-releasing hormone agonist (GnRHa). The Child Stress Scale (CSS) was used for 10 unrelated girls with CPP before and after the first year of GnRHa treatment. The CSS is divided into four subscales (physical, psychological, psychological with depressive component and psychophysiological reactions). Through a quantitative analysis, it is possible to classify stress into four stages: alarm, resistance, near-exhaustion and exhaustion. At diagnosis, 90% of the girls showed stress levels scores at the alarm or resistance stage on at least one subscale, mostly in terms of physical and psychological reactions. The mean total stress score was significantly higher before when compared to after GnRHa treatment (43.4±15.6 vs. 28.9±9.7; p<0.05). The mean stress scores obtained in all subscales, except the one on psychophysiological reactions, were significantly higher before GnRHa treatment. Higher stress levels were a common finding in girls with CPP before treatment. The significant stress level reduction after pubertal suppression reinforces the idea that sexual precocity is a stressful condition in children. The CSS might be a useful tool for psychological assessment of patients with CPP.

A pivotal event in the onset of puberty in humans is the reemergence of the pulsatile release of the gonadotropin-releasing hormone (GnRH) from hypothalamic neurons. Pathways governing GnRH ontogeny and physiology have been discovered by studying animal models and humans with reproductive disorders. Recent human studies implicated the activation of kisspeptin and its cognate receptor (KISS1/KISS1R) and the inactivation of MKRN3 in the premature reactivation of GnRH secretion, causing central precocious puberty (CPP). MKRN3, an imprinted gene located on the long arm of chromosome 15, encodes makorin ring finger protein 3, which is involved in ubiquitination and cell signaling. The MKRN3 protein is derived only from RNA transcribed from the paternally inherited copy of the gene due to maternal imprinting. Currently, MKRN3 defects represent the most frequent known genetic cause of familial CPP. In this review, we explored the clinical, hormonal and genetic aspects of children with sporadic or familial CPP caused by mutations in the kisspeptin and MKRN3 systems, essential genetic factors for pubertal timing.

Abstract Context The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. Objective This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Methods We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. Results MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). Conclusion We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

The gonadotropin releasing hormone (GnRH) secreting hypothalamic hamartoma (HH) is a congenital malformation consisting of a heterotopic mass of nervous tissue that contains GnRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle. HH is a well recognised cause of gonadotropin dependent precocious puberty (GDPP). Long term data are presented on eight children (five boys and three girls) with GDPP due to HH. Physical signs of puberty were observed before 2 years of age in all patients. At presentation with sexual precocity, the mean height standard deviation (SD) for chronological age was +1.60 (1.27) and the mean height SD for bone age was −0.92 (1.77). Neurological symptoms were absent at presentation and follow up. The hamartoma diameter ranged from 5 to 18 mm and did not change in six patients who had magnetic resonance imaging follow up. All patients were treated clinically with GnRH agonists (GnRH-a). The duration of treatment varied from 2.66 to 8.41 years. Seven of the eight children had satisfactory responses to treatment, shown by regression of pubertal signs, suppression of hormonal levels, and improvement of height SD for bone age and predicted height. One patient had a severe local reaction to GnRH-a with failure of hormonal suppression and progression of pubertal signs. It seems that HH is benign and that GnRH-a treatment provides satisfactory and safe control for most children with GDPP due to HH.

In normal males, luteinizing hormone (LH) regulates the function of Leydig cells and, hence, male sexual differentiation, pubertal androgenization, male sexual function, and fertility. Abnormalities in the function of Leydig cells result in primary hypogonadism and varying degrees of male pseudohermaphroditism. In these patients, Leydig cells are absent, hypoplastic, or unresponsive to stimulation with human chorionic gonadotropin (hCG), and studies of testicular-biopsy samples from some patients have revealed the absence of LH receptors. In normal women, LH stimulates the theca cells to produce androgen precursors for aromatization to estradiol by granulosa cells during the follicular phase of the menstrual cycle. Subsequently, during its midcycle surge, LH promotes follicular maturation and ovulation, and during the luteal phase, LH induces the formation of the corpus luteum and stimulates progesterone secretion. Thus, abnormalities in the LH receptor would be expected to result in partial ovarian failure characterized by defective folliculogenesis, anovulation, the absence of a luteal phase, delayed or incomplete feminization at puberty, amenorrhea, and infertility. The human LH receptor belongs to the G protein-coupled superfamily of receptors with seven transmembrane domains. A homozygous missense inactivating mutation in the sixth transmembrane domain of the LH-receptor gene has been identified in two male pseudohermaphrodite siblings with female phenotypes and Leydig-cell hypoplasia. In this report we describe two unrelated kindreds with defects in the differentiation of male external genitalia in genetically male family members and amenorrhea in a genetically female family member. DNA-sequencing analysis revealed homozygous mutations of the LH-receptor gene in each kindred that impaired the function of the LH receptor and prevented it from transmitting the hormonal signal in the testes and ovaries of the affected patients.

Mutations in the 3β-hydroxysteroid dehydrogenase (3β-HSD) type II gene have been reported in a small number of affected females. We report a 46,XX girl born to consanguineous parents from Chile. At birth, she had normal but hyperpigmented female external genitalia. At 60 days she presented salt loss. At 20 months, the diagnosis of classic salt-losing 3β-HSD deficiency was made based on an elevated serum 17-hydroxypregnenolone concentration and a high 17 hydroxypregnenolone/17-hydroxyprogesterone ratio. Genomic DNA was amplified by PCR and screened for mutations by denaturing gradient gel electrophoresis and directly sequenced. A novel homozygous E135* mutation was found in the 3β-HSD type II gene of the patient while her parents were heterozygotes. This novel nonsense homozygous E135* mutation led to encode a predicted truncated 134 amino acid protein instead of the native 371 amino acid 3β-HSD type II protein. This predicted product is consistent with the severe 3β-HSD deficiency in this girl. Hum Mutat 12:139, 1998. © 1998 Wiley-Liss, Inc.

Mutations in the 3β‐hydroxysteroid dehydrogenase (3β‐HSD) type II gene have been reported in a small number of affected females. We report a 46,XX girl born to consanguineous parents from Chile. At birth, she had normal but hyperpigmented female external genitalia. At 60 days she presented salt loss. At 20 months, the diagnosis of classic salt‐losing 3β‐HSD deficiency was made based on an elevated serum 17‐hydroxypregnenolone concentration and a high 17 hydroxypregnenolone/17‐hydroxyprogesterone ratio. Genomic DNA was amplified by PCR and screened for mutations by denaturing gradient gel electrophoresis and directly sequenced. A novel homozygous E135* mutation was found in the 3β‐HSD type II gene of the patient while her parents were heterozygotes. This novel nonsense homozygous E135* mutation led to encode a predicted truncated 134 amino acid protein instead of the native 371 amino acid 3β‐HSD type II protein. This predicted product is consistent with the severe 3β‐HSD deficiency in this girl. Hum Mutat 12:139, 1998. © 1998 Wiley‐Liss, Inc.