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Hypogonadism, female [keywords]
- Neonatal monosodium glutamate treatment counteracts circadian arrhythmicity induced by phase shifts of the light-dark cycle in female and male Siberian hamsters. [JOURNAL ARTICLE]
- Brain Res 2013 May 20.
Studies of rats and voles suggest that distinct pathways emanating from the anterior hypothalamic-retrochiasmatic area and the mediobasal hypothalamic arcuate nucleus independently generate ultradian rhythms (URs) in hormone secretion and behavior. We evaluated the hypothesis that destruction of arcuate nucleus (ARC) neurons, in concert with dampening of suprachiasmatic nucleus (SCN) circadian rhythmicity, would compromise the generation of ultradian rhythms (URs) of locomotor activity. Siberian hamsters of both sexes treated neonatally with monosodium glutamate (MSG) that destroys ARC neurons were subjected in adulthood to a circadian disrupting phase-shift protocol (DPS) that produces SCN arrhythmia. MSG treatments induced hypogonadism and obesity, and markedly reduced the size of the optic chiasm and primary optic tracts. MSG-treated hamsters exhibited normal entrainment to the light-dark cycle, but MSG treatment counteracted the circadian arrhythmicity induced by the DPS protocol: only 6% of MSG-treated hamsters exhibited circadian arrhythmia, whereas 50% of control hamsters were circadian disrupted. In MSG-treated hamsters that retained circadian rhythmicity after DPS treatment, quantitative parameters of URs appeared normal, but in the 2MSG-treated hamsters that became circadian arrhythmic after DPS, both dark-phase and light-phase URs were abolished. Although preliminary, these data are consistent with reports in voles suggesting that the combined disruption of SCN and ARC function impairs the expression of behavioral URs. The data also suggest that light thresholds for entrainment of circadian rhythms may be lower than those required to disrupt circadian organization.
- Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination. [JOURNAL ARTICLE]
- Brain Dev 2013 May 18.
OBJECTIVE:Congenital white matter disorders are a heterogeneous group of hypomyelination disorders affecting the white matter of the brain. Recently, mutations in the genes encoding the subunits of RNA polymerase III (Pol III), POLR3A and POLR3B, have been identified as new genetic causes for hypomyelinating disorders.
METHOD:Whole-exome sequencing was applied to identify responsible gene mutations in a 29-year-old female patient showing hypomyelination of unknown cause. To investigate the pathological mechanism underlying the hypomyelination in this patient, the expression level of 7SL RNA, a transcriptional target of Pol III, was analyzed in cultured skin fibroblasts derived from the patient with POLR3A mutations.
RESULTS:Novel compound heterozygous mutations of POLR3A were identified in the patient, who started to show cerebellar signs at 3years, lost ambulation at 7years, and became bedridden at 18years. Brain magnetic resonance imaging showed severe volume loss in the brainstem, the cerebellum, and the white matter associated with hypomyelination. In addition to hypodontia and hypogonadism, she showed many pituitary hormone-related deficiencies. The expression level of 7SL RNA in cultured skin fibroblasts derived from this patient showed no significant abnormality.
CONCLUSION:The many pituitary hormone-related deficiencies identified in this patient may be an essential finding for the Pol III-related leukodystrophies spectrum. Further investigation is needed for a better understanding of the disease mechanism.
- Metabolic Disorders and Diabetic Complications in Spontaneously Diabetic Torii Lepr (fa) Rat: A New Obese Type 2 Diabetic Model. [Journal Article]
- J Diabetes Res 2013.:948257.
Spontaneously Diabetic Torii Lepr (fa) (SDT fatty) rat, established by introducing the fa allele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with SDT rats. With early incidence of diabetes mellitus, diabetic complications, such as nephropathy, retinopathy, and neuropathy, in SDT fatty rats were seen at younger ages compared to those in the SDT rats. In this paper, we overview pathophysiological features in SDT fatty rats and also describe new insights regarding the hematology, blood pressure, renal complications, and sexual dysfunction. The SDT fatty rats showed an increase of leukocytes, especially the monocyte count, prominent hypertension associated with salt drinking, end-stage renal disease with aging, and hypogonadism. Unlike other diabetic models, the characteristic of SDT fatty rat is to present an incidence of diabetes in females, hypertension, and retinopathy. SDT fatty rat is a useful model for analysis of various metabolic disorders and the evaluation of drugs related to metabolic disease.
- Submicroscopic deletion involving the fibroblast growth factor receptor 1 gene in a patient with combined pituitary hormone deficiency. [JOURNAL ARTICLE]
- Endocr J 2013 May 9.
Combined pituitary hormone deficiency (CPHD), isolated hypogonadotropic hypogonadism (IHH), Kallmann syndrome (KS), and septo-optic dysplasia (SOD) are genetically related conditions caused by abnormal development of the anterior midline in the forebrain. Although mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been implicated in the development of IHH, KS, and SOD, the relevance of FGFR1 abnormalities to CPHD remains to be elucidated. Here, we report a Japanese female patient with CPHD and FGFR1 haploinsufficiency. The patient was identified through copy-number analyses and direct sequencing of FGFR1 performed for 69 patients with CPHD. The patient presented with a combined deficiency of GH, LH and FSH, and multiple neurological abnormalities. In addition, normal TSH values along with a low free T4 level indicated the presence of central hypothyroidism. Molecular analyses identified a heterozygous ~8.5 Mb deletion involving 56 genes and pseudogenes. None of these genes except FGFR1 have been associated with brain development. No FGFR1 abnormalities were identified in the remaining 68 patients, although two patients carried nucleotide substitutions (p.V102I and p.S107L) that were assessed as benign polymorphism by in vitro functional assays. These results indicate a possible role of FGFR1 in anterior pituitary function and the rarity of FGFR1 abnormalities in patients with CPHD.
- Revisiting hyper- and hypo-androgenism by tandem mass spectrometry. [JOURNAL ARTICLE]
- Rev Endocr Metab Disord 2013 Apr 26.
Modern endocrinology is living a critical age of transition as far as laboratory testing and biochemical diagnosis are concerned. Novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for steroid measurement in biological fluids have abundantly demonstrated their analytical superiority over immunometric platforms that until now have dominated the world of steroid hormones determination in clinical laboratories. One of the most useful applications of LC-MS/MS is in the hypogonadism and hyperandrogenism field: LC-MS/MS has proved particularly suitable for the detection of low levels of testosterone typical of women and children, and in general more reliable in accurately determining hypogonadal male levels. This technique also offers increased informative power by allowing multi-analytical profiles that give a more comprehensive picture of the overall hormonal asset. Several LC-MS/MS methods for testosterone have been published in the last decade, some of them included other androgen or more comprehensive steroid profiles. LC-MS/MS offers the concrete possibility of achieving a definitive standardization of testosterone measurements and the generation of widely accepted reference intervals, that will set the basis for a consensus on the diagnostic value of biochemical testing. The present review is aimed at summarizing technological advancements in androgen measurements in serum and saliva. We also provide a picture of the state of advancement of standardization of testosterone assays, of the redefinition of androgen reference intervals by novel assays and of studies using LC-MS/MS for the characterization and diagnosis of female hyperandrogenism and male hypogonadism.
- Duplication of dosage sensitive sex reversal area in a 46, XY patient with normal sex determining region of Y causing complete sex reversal. [JOURNAL ARTICLE]
- J Pediatr Endocrinol Metab 2013 Apr 22.:1-5.
Background:The sex chromosome composition of the primordial gonad, either 46XX or 46XY, determines its differentiation as ovaries or testes. Local hormones secreted by developing gonads and tissue specific transcription factors influence the differentiation of external and internal genital structures. Dosage sensitive sex reversal adrenal hypoplasia congenita critical region (DAX1) on Xp21 is a gene which is expressed in the developing adrenals, gonads, hypothalamus and pituitary gland. Duplication of this area causes dosage sensitive male-to-female sex reversal while mutation or deletion leads to adrenal hypoplasia congenita with hypogonadotropic hypogonadism in affected males.
Aim:To report a case with duplication of the X chromosome segment within the region of Xp21.1-22.2 resulting in 46 XY sex reversal and a literature review on DAX1 and dosage sensitive sex reversal (DSS). Methods and results: We present the clinical history, physical findings, laboratory, and imaging study results in a newborn baby. This infant was sex assigned as female at birth and had normal female external genitalia. Chromosome analysis was done due to multiple minor malformations and showed a karyotype of 46 Xp+Y. Fluorescent in situ hybridization analysis revealed the duplication in the DSS area.
Conclusion:Duplication of the DAX1 gene on the X chromosome with normal sex determining region of Y (SRY) results in 46 XY sex reversal. This was inherited from the mother who had normal ovarian function. Additional problems include growth failure, mental retardation and multiple congenital anomalies. The baby did not have a mutation or deletion of DAX1, which would have caused adrenal insufficiency and hypogonadism.
- Mutations in NR5A1 and PIN1 associated with idiopathic hypogonadotropic hypogonadism. [JOURNAL ARTICLE]
- J Pediatr Endocrinol Metab 2012 Jun 7.:1-6.
Objective:The objective of this study is to test the hypothesis that mutations in NR5A1 and PIN1 cause disorders of gonadotropin-gonadal system development and function.
Methods:DNA sequencing of the coding sequence and splice sites of NR5A1 and PIN1 was performed for 50 subjects with sporadic idiopathic hypogonadotropic hypogonadism (IHH) in the Department of Pediatrics, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology. None of the affected subjects had clinical signs of adrenal insufficiency.
Results:NR5A1 and PIN1 mutations were found in seven of 50 cases. These 7 individuals presented with severely low serum concentration of testosterone or estradiol and gonadotropin. To date, adrenal insufficiency has not occurred in any of these patients.
Conclusions:NR5A1 or PIN1 mutations should be considered in male or female IHH patients with normal karyotype and without insufficiency of adrenal function.
- Atypical presentations of Wolframs syndrome. [Journal Article]
- Indian J Endocrinol Metab 2012 Dec; 16(Suppl 2):S504-5.
BACKGROUND:Wolfram syndrome is a rare hereditary or sporadic neurodegenerative disorder also known as DIDMOAD. The classically described presentation is of insulin-dependent diabetes, followed by optic atrophy, central diabetes insipidus, and sensory neural deafness. Also included are less well-described presentations of Wolframs syndrome. We here present three cases of atypical presentation of this syndrome. CASE 1: A 15-year-old boy with insulin-dependent diabetes was presented for evaluation of depressive symptoms associated with suicidal tendency. Neuropsychiatric manifestations are described with Wolframs syndrome, and wolframin gene, in recessive inheritance, is associated with psychiatric illnesses without other manifestations of Wolframs syndrome. CASE 2: A 17-year-old diabetic boy on insulin with good control of blood sugar presented for evaluation of delayed puberty. Central hypogonadism and other anterior pituitary hormone dysfunctions are the less publicized hormone dysfunctions in Wolframs syndrome. CASE 3: A 23-year-old female who was on insulin for diabetes for the past 14 years, got admitted for evaluation of sudden loss of vision. This patient had developed a vitreous hemorrhage and, on evaluation, was found to have optic atrophy, sensory neural hearing loss, and diabetes insipidus, and presented differently from the gradual loss of vision described in Wolframs syndrome.
CONCLUSION:Wolframs syndrome being a multisystem degenerative disorder can have myriad other manifestations than the classically described features. Neuropsychiatric manifestations, depression with suicidal risk, central hypogonadism, and secondary adrenal insufficiency are among the less well-described manifestations of this syndrome.
- Short-term effects of continuous positive airway pressure on sex hormones in men and women with sleep apnoea syndrome. [JOURNAL ARTICLE]
- Andrologia 2013 Mar 30.
Patients with sleep apnoea syndrome (SAS) suffer from symptoms of hypogonadism. Besides surgical interventions, in some cases, the standard care of SAS for most patients is continuous positive airway pressure (CPAP). Studies focusing on the long-term effects of CPAP on testosterone levels revealed conflicting results. None of the studies included female patients with SAS. The aim of our study was to analyse and compare sex hormone levels in saliva before and after a night without and with CPAP in women and men with SAS. The results were negative. One night with CPAP did not affect the dynamics of sex hormones, neither in men nor in women. Future studies should focus on long-term effects of CPAP in both genders.
- Poor socio-economic status in 47,XXX - An unexpected effect of an extra X chromosome. [JOURNAL ARTICLE]
- Eur J Med Genet 2013 Mar 28.
One of the most common sex chromosomal abnormalities in females is 47,XXX syndrome, which is characterized by tall stature and reduced IQ, but with a variable phenotype. In order to elaborate on the characteristics of this syndrome, we undertook an investigation in all diagnosed 47,XXX females at risk in Denmark and compared their socio-economic status with an age-matched cohort of the female background population as well as with all Danes diagnosed with Turner syndrome. We focused on cohabitation, motherhoods, income, education, retirement and convictions. Furthermore, we investigated whether some of these parameters influenced the increased mortality identified previously. Thus, socio-economic data were retrieved in 108 47,XXX persons, 10,297 controls, and 831 with Turner syndrome. Comparing the 47,XXX persons with their controls, we identified significantly decreased numbers of first partnership, number of mothers, and number of persons with an education in 47,XXX persons. Significantly more 47,XXX persons retired. In the younger age groups an increased number had income below the median among controls. The increased mortality identified previously was not explained by the reduced number of partnerships or the reduced number of persons with an education. Comparing the 47,XXX persons with Turner syndrome persons, we identified increased number of first partnership, number of mothers, and reduced level of education. We hypothesize that the significantly decreased number of 47,XXX persons becoming mothers could be due to hypogonadism in some. The affected socio-economic status suggests that the presence of an extra X chromosome has more detrimental effects than previously appreciated.