RESUMO
Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney. This review outlines the evidence for a gender differential expression and activation of renal corticosteroid signaling pathways in the mammalian fetus and neonate, from mouse to human, that may favor mineralocorticoid signaling in females and glucocorticoid signaling in males. Determining the effects of such differences may shed light on short term and long term pathophysiological consequences, markedly for males.
Assuntos
Corticosteroides/metabolismo , Rim/embriologia , Aldosterona/metabolismo , Animais , Pressão Sanguínea/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Glucocorticoides/metabolismo , Humanos , Hipertensão/metabolismo , Rim/metabolismo , Mineralocorticoides/metabolismo , Organogênese , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Caracteres Sexuais , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVE: SRY-negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long-term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported. DESIGN: Retrospective description of sixteen 46,XX T/OTDSD patients. RESULTS: Sixteen 46,XX SRY-negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP-array, next-generation sequencing and whole-exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient. CONCLUSIONS: This study presents a population of patients with 46,XX SRY-negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls.
Assuntos
Transtornos Ovotesticulares do Desenvolvimento Sexual , Feminino , Humanos , Recém-Nascido , Masculino , Ovário , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Estudos Retrospectivos , TestículoRESUMO
Renal and cardiovascular complications of prematurity are well established, notably the development of hypertension in adulthood. However, the underlying molecular mechanisms remain poorly understood. Our objective was to investigate the impact of prematurity on the ontogenesis of renal corticosteroid pathways, to evaluate its implication in perinatal renal complications and in the emergence of hypertension in adulthood. Swiss CD1 pregnant mice were injected with lipopolysaccharides at 18 days of gestation (E18) to induce prematurity at E18.5. Pups were sacrificed at birth, 7 days and 6 months of life. Second (F2) and third (F3) generations, established by mating prematurely born adult females with wild-type males, were also analyzed. Former preterm males developed hypertension at M6 (P < 0.0001). We found robust activation of renal corticosteroid target gene transcription at birth in preterm mice (αENaC (+45%), Gilz (+85%)), independent of any change in mineralocorticoid or glucocorticoid receptor expression. The offspring of the preterm group displayed increased blood pressure in F2 and F3, associated with increased renal Gilz mRNA expression, despite similar MR or GR expression and plasma corticosteroid levels measured by LC-MS/MS. Gilz promoter methylation measured by methylated DNA immunoprecipitation-qPCR was reduced with a negative correlation between methylation and expression (P = 0.0106). Our study demonstrates prematurity-related alterations in renal corticosteroid signaling pathways, with transgenerational inheritance of blood pressure dysregulation and epigenetic Gilz regulation up to the third generation. This study provides a better understanding of the molecular mechanisms involved in essential hypertension, which could partly be due to perinatal epigenetic programming from previous generations.
Assuntos
Epigênese Genética/genética , Hipertensão/genética , Nascimento Prematuro/genética , Animais , Pressão Sanguínea/genética , Metilação de DNA/genética , Modelos Animais de Doenças , Epigenômica/métodos , Feminino , Expressão Gênica/genética , Masculino , Camundongos , Gravidez , Receptores de Glucocorticoides/genética , Transcrição Gênica/genéticaRESUMO
OBJECTIVE: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. METHODS: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. RESULTS: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). CONCLUSION: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.
Assuntos
Cromossomos Humanos X , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Genitália/anormalidades , Mosaicismo , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/patologia , Adulto , Azoospermia/diagnóstico , Azoospermia/genética , Estatura , Criança , Feminino , Seguimentos , França , Genitália/crescimento & desenvolvimento , Genitália/patologia , Transtornos do Crescimento/genética , Humanos , Recém-Nascido , Cariotipagem , Estudos Longitudinais , Masculino , Monossomia , Fenótipo , Gravidez , Diagnóstico Pré-Natal , Puberdade , Estudos RetrospectivosRESUMO
Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP) and heart rate (HR) were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR), and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance. The role of sex hormones in the regulation of these genes was also investigated in differentiated KC3AC1 renal cells. Additionally, renal expression of the 11 ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) protein, a regulator of mineralocorticoid specificity, was measured by immunoblotting and its activity was indirectly assessed in the plasma using liquid-chromatography coupled to mass spectrometry in tandem (LC-MSMS) method. SBP and HR were found to be significantly lower in females compared to males. This was accompanied by a sex- and tissue-specific expression profile throughout renal development of the mineralocorticoid target genes serum and glucocorticoid-regulated kinase 1 (Sgk1) and glucocorticoid-induced leucine zipper protein (Gilz), together with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA expression. We demonstrate a tissue-specific, sex-dependent and developmentally-regulated pattern of expression of the mineralocorticoid pathway that could have important implications in physiology and pathology.