RESUMEN
CONTEXT: Follicle-stimulating hormone (FSH) plays an essential role in gonadal function. Loss-of-function mutations in the follicle-stimulating hormone receptor (FSHR) are an infrequent cause of primary ovarian failure. OBJECTIVE: To analyze the molecular physiopathogenesis of a novel mutation in the FSHR identified in a woman with primary ovarian failure, employing in vitro and in silico approaches, and to compare the features of this dysfunctional receptor with those shown by the trafficking-defective D408Y FSHR mutant. METHODS: Sanger sequencing of the FSHR cDNA was applied to identify the novel mutation. FSH-stimulated cyclic adenosine monophosphate (cAMP) production, ERK1/2 phosphorylation, and desensitization were tested in HEK293 cells. Receptor expression was analyzed by immunoblotting, receptor-binding assays, and flow cytometry. Molecular dynamics simulations were performed to determine the in silico behavior of the mutant FSHRs. RESULTS: A novel missense mutation (I423T) in the second transmembrane domain of the FSHR was identified in a woman with normal pubertal development but primary amenorrhea. The I423T mutation slightly impaired plasma membrane expression of the mature form of the receptor and severely impacted on cAMP/protein kinase A signaling but much less on ß-arrestin-dependent ERK1/2 phosphorylation. Meanwhile, the D408Y mutation severely affected membrane expression, with most of the FSH receptor located intracellularly, and both signal readouts tested. Molecular dynamics simulations revealed important functional disruptions in both mutant FSHRs, mainly the loss of interhelical connectivity in the D408Y FSHR. CONCLUSIONS: Concurrently, these data indicate that conformational differences during the inactive and active states account for the distinct expression levels, differential signaling, and phenotypic expression of the I423T and D408Y mutant FSHRs.
Asunto(s)
Insuficiencia Ovárica Primaria/genética , Receptores de HFE/genética , Adulto , Amenorrea/genética , Amenorrea/metabolismo , Sustitución de Aminoácidos , Familia , Femenino , Hormona Folículo Estimulante/farmacología , Células HEK293 , Humanos , Isoleucina/genética , Mutación con Pérdida de Función/genética , Modelos Moleculares , Mutación Missense , Linaje , Insuficiencia Ovárica Primaria/metabolismo , Receptores de HFE/agonistas , Receptores de HFE/química , Receptores de HFE/metabolismo , Treonina/genéticaRESUMEN
Functional hypothalamic amenorrhoea (FHA) can occur due to the independent or combined effects of psychogenic and energetic stressors. In exercising women, research has primarily focused on energy deficiency as the cause of FHA while psychological stressors have been ignored. To assess both psychological and metabolic factors associated with FHA in exercising women, we performed across-sectional comparison of 61 exercising women (≥2 hours/week, age 18-35 years, BMI 16-25kg/m2), who were eumenorrheic or amenorrhoeic confirmed by daily urine samples assayed for reproductive hormone metabolites. Psychological factors and eating behaviours were assessed by self-report questionnaires. Exercising women with FHA had lower resting metabolic rate (p=0.023), T3 (p<0.001), T4 (p=0.013), leptin (p=0.002), higher peptide YY (p<0.001), greater drive for thinness (p=0.017), greater dietary cognitive restraint (p<0.001), and displayed dysfunctional attitudes, i.e., need for social approval (p=0.047) compared to eumenorrheic women. Amenorrhoeic women displayed asignificant positive correlation between the need for social approval and drive for thinness with indicators of stress, depression, and mood, which was not apparent in eumenorrheic women. In exercising women with FHA, eating behaviours are positively related to indicators of psychological stress and depression.
Asunto(s)
Amenorrea/metabolismo , Amenorrea/psicología , Ejercicio Físico/psicología , Conducta Alimentaria/psicología , Trastornos de Alimentación y de la Ingestión de Alimentos/metabolismo , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Estrés Psicológico , Adolescente , Adulto , Amenorrea/fisiopatología , Metabolismo Basal , Índice de Masa Corporal , Estudios Transversales , Depresión/psicología , Dieta , Ejercicio Físico/fisiología , Trastornos de Alimentación y de la Ingestión de Alimentos/fisiopatología , Femenino , Humanos , Hipotálamo/fisiología , Ciclo Menstrual , Delgadez/psicología , Adulto JovenRESUMEN
BACKGROUND/AIMS: Splicing CYP19 gene variants causing aromatase deficiency in 46,XX disorder of sexual development (DSD) patients have been reported in a few cases. A misbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast development but an incomplete sex maturation progress. The aim of this study was to functionally characterize a novel CYP19A1 intronic homozygote mutation (IVS9+5G>A) in a 46,XX DSD girl presenting spontaneous breast development and primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. METHODS: Genomic DNA analysis, splicing prediction programs, splicing assays, and in vitro protein expression and enzyme activity analyses were carried out. CYP19A1 mRNA expression in human steroidogenic tissues was also studied. RESULTS: A novel IVS9+5G>A homozygote mutation was found. In silico analysis predicts the disappearance of the splicing donor site in intron 9, confirmed by patient peripheral leukocyte cP450arom and in vitro studies. Protein analysis showed a shorter and inactive protein. The intron 9 transcript variant was also found in human steroidogenic tissues. CONCLUSIONS: The mutation IVS9+5G>A generates a splicing variant that includes intron 9 which is also present in normal human steroidogenic tissues, suggesting that a misbalance between normal and aberrant splicing variants might occur in target tissues, explaining the clinical phenotype in the affected patient.
Asunto(s)
Amenorrea/genética , Aromatasa/deficiencia , Adolescente , Glándulas Suprarrenales/metabolismo , Amenorrea/metabolismo , Animales , Aromatasa/genética , Aromatasa/metabolismo , Células COS , Línea Celular , Chlorocebus aethiops , Femenino , Humanos , Masculino , Ratones , Mutación , Fenotipo , Placenta/metabolismo , Embarazo , Empalme de Proteína , Testículo/metabolismoRESUMEN
The aim of this manuscript was to review the knowledge about leptin, detailing its relationship with energetic intake and physical activity. Leptin is an adipocyte hormone, recognized mainly for its putative role in control of energy expenditure, food intake, body weight and reproductive function. Leptin has still important peripheral actions, including its role on the ovarian tissue. The intracellular signaling mechanisms are recognized in hypothalamus, but in peripheral tissue are not fully understood. The exercise, when practiced by women, if not appropriately planned according to food intake, can modify the leptin release. When energy imbalances induced by exercise and/or deficient food ingestion occurs, low leptin levels are observed, leading to a reduction in GnRH (gonadotropin-release hormone), in LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in pituitary, and consequently a minor release of ovarian estrogens. This process is named hypothalamic amenorrhea, and has repercussions in the woman's health. In this perspective, it is important to emphasize the need to evaluate the energy expenditure from exercise and to formulate adequate alimentary plans to these individuals.
Asunto(s)
Amenorrea/metabolismo , Dieta , Metabolismo Energético/fisiología , Ejercicio Físico/fisiología , Leptina/fisiología , Deportes/fisiología , Tejido Adiposo/metabolismo , Adolescente , Adulto , Factores de Edad , Biomarcadores/metabolismo , Índice de Masa Corporal , Restricción Calórica , Niño , Femenino , Humanos , Hipotálamo/metabolismo , Obesidad/metabolismoRESUMEN
O presente manuscrito teve por objetivo realizar uma revisão bibliográfica acerca do papel da leptina no balanço energético, no exercício físico e na incidência da amenorréia do esforço. A leptina é um hormônio secretado pelo tecido adiposo, reconhecido principalmente por sua ação adipostática sobre o sistema nervoso central. Esse hormônio sinaliza o hipotálamo a respeito das reservas energéticas, modulando o funcionamento dos eixos hormonais que envolvam o hipotálamo e a hipófise. A leptina tem ainda ações periféricas importantes, incluindo seu papel sobre o tecido ovariano. Os mecanismos de sinalização intracelular desse hormônio foram identificados no hipotálamo, porém em tecidos periféricos há necessidade de maiores investigações. Existe certo consenso de que quando o exercício e a ingestão alimentar são capazes de promover um balanço energético negativo, as concentrações plasmáticas de leptina diminuem, alterando conseqüentemente: a liberação hipotalâmica de GnRH (fator hipotalâmico de liberação de gonadotrofinas); a liberação hipofisária de LH (hormônio luteinizante) e FSH (hormônio folículo-estimulante). Como resultado, há menor liberação de estrógenos ovarianos. Esse processo pode iniciar a chamada amenorréia hipotalâmica funcional, com repercussões na saúde da mulher. Nessa perspectiva, a avaliação do gasto energético e a elaboração de um plano alimentar adequado em atletas são fundamentais.
The aim of this manuscript was to review the knowledge about leptin, detailing its relationship with energetic intake and physical activity. Leptin is an adipocyte hormone, recognized mainly for its putative role in control of energy expenditure, food intake, body weight and reproductive function. Leptin has still important peripheral actions, including its role on the ovarian tissue. The intracellular signaling mechanisms are recognized in hypothalamus, but in peripheral tissue are not fully understood. The exercise, when practiced by women, if not appropriately planned according to food intake, can modify the leptin release. When energy imbalances induced by exercise and/or deficient food ingestion occurs, low leptin levels are observed, leading to a reduction in GnRH (gonadotropin-release hormone), in LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in pituitary, and consequently a minor release of ovarian estrogens. This process is named hypothalamic amenorrhea, and has repercussions in the woman's health. In this perspective, it is important to emphasize the need to evaluate the energy expenditure from exercise and to formulate adequate alimentary plans to these individuals.
Asunto(s)
Adolescente , Adulto , Niño , Femenino , Humanos , Amenorrea/metabolismo , Dieta , Metabolismo Energético/fisiología , Ejercicio Físico/fisiología , Leptina/fisiología , Deportes/fisiología , Factores de Edad , Tejido Adiposo/metabolismo , Índice de Masa Corporal , Biomarcadores/metabolismo , Restricción Calórica , Hipotálamo/metabolismo , Obesidad/metabolismoRESUMEN
BACKGROUND: The main reason for discontinuation of the levonorgestrel-releasing intrauterine system (LNG-IUS) is unpredictable bleeding pattern. METHODS: The objective of the study was to evaluate the endometrial histology, microvascular density and calibre, and the quantification of matrix metalloproteinase (MMP-3) in long-term users of LNG-IUS, with and without bleeding. Endometrial biopsies were obtained from 58 healthy women, 29 who maintained some degree of endometrial bleeding and 29 who were amenorrhoeic. RESULTS: In the histological analysis, the majority of samples displayed a progestin-modified appearance. The major glandular diameter and the perimeter were significantly greater in the group of women with amenorrhoea. A significantly higher number of leukocytes was found in the group with bleeding (P = 0.014). No significant correlation was observed between the microvascular density or calibre and the bleeding pattern. MMP-3 showed a significantly higher number of reactive cells (P = 0.005) in the group who maintained some degree of bleeding. CONCLUSIONS: Women using LNG-IUS who maintained endometrial bleeding during its use presented a higher number of leukocytes and MMP-3 in the endometrium when compared to women using LNG-IUS who became amenorrhoeic. However, the results did not provide evidence for microvascular pattern changes.
Asunto(s)
Amenorrea/patología , Anticonceptivos Femeninos/efectos adversos , Endometrio/patología , Levonorgestrel/efectos adversos , Metaloproteinasa 3 de la Matriz/metabolismo , Menstruación/efectos de los fármacos , Adulto , Amenorrea/metabolismo , Biopsia , Anticonceptivos Femeninos/administración & dosificación , Endometrio/irrigación sanguínea , Endometrio/enzimología , Femenino , Humanos , Leucocitos/patología , Levonorgestrel/administración & dosificación , Microcirculación/efectos de los fármacos , Microcirculación/patología , Células del Estroma/enzimologíaRESUMEN
O propósito desta revisäo é focalizar o exercício como modulador da reproduçäo humana, resumir e integrar os dados atuais referentes ao eixo hipotálamo-hipófise-gonadal na mulher atleta. A prevalência de disfunçäo menstrual, tal como fase lútea deficiente, oligomenorréia, amenorréia e retardo puberal, é maior entre o grupo de mulheres atletas quando comparado à populaçäo geral. Vários fatores podem predispor e contribuir para o desenvolvimento das irregularidades menstruais durante o programa de atividade física, sendo considerados fatores de risco, entre eles, baixo peso, teor de gordura corporal e estados hipoestrogênicos. O hipoestrogenismo pode afetar o pico de massa óssea na puberdade e acarretar perda óssea prematura irreversível. O artigo revisa os efeitos fisiológicos do treinamento físico nos vários sistemas endócrinos e aborda informaçöes clínicas a respeito dos distúrbios hormonais específicos da mulher atleta.
Asunto(s)
Humanos , Femenino , Ejercicio Físico/fisiología , Hormonas/metabolismo , Amenorrea/metabolismo , Anovulación/metabolismo , Cuerpo Lúteo/fisiopatología , Pubertad Precoz/metabolismo , Reproducción/fisiología , Sistema Hipotálamo-Hipofisario/metabolismoRESUMEN
The effects of insulin on the metabolism of U14C-glucose in uteri isolated from ovariectomized and non-ovariectomized rats receiving a restricted diet (50% of the normal food intake) for 25 days, were studied. As a result of food restriction, the production of 14CO2 diminishes in intact rats, while results are reversed in ovariectomized ones. Various concentrations of insulin were added to the medium, but only 0.50 IU. ml(-1)was effective in increasing glucose metabolism in intact rats receiving a restricted diet; neither underfed castrated animals nor control ones receiving a normal diet, reacted to this concentration. The increase of 14CO2 produced by insulin is not affected by acetyl salicylic acid. Insulin does not alter the effect of underfeeding over arachidonic acid metabolism. On the contrary, the increase in glucose metabolism was blocked by N(G)methyl-L-arginine or by hemoglobin, increased with the addition of L arginine and is not affected by acetyl salicylic acid. Hemoglobin and L-arginine show no effects without insulin. We can conclude that the stimulating effect of insulin on glucose metabolism in uteri isolated from intact rats subjected to dietary restriction, is nitric oxide dependent.
Asunto(s)
Privación de Alimentos , Glucosa/metabolismo , Insulina/farmacología , Óxido Nítrico/fisiología , Ovariectomía , Útero/efectos de los fármacos , Amenorrea/etiología , Amenorrea/metabolismo , Animales , Ácido Araquidónico/metabolismo , Arginina/farmacología , Aspirina/farmacología , Diestro , Relación Dosis-Respuesta a Droga , Eicosanoides/metabolismo , Metabolismo Energético/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Hemoglobinas/farmacología , Insulina/administración & dosificación , Miometrio/efectos de los fármacos , Miometrio/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Ratas , Ratas Wistar , Útero/metabolismo , omega-N-Metilarginina/farmacologíaRESUMEN
OBJECTIVE: To analyze the influence of weight on gonadotrophin response after chlormadinone (hydroxyprogesterone derivative) induced uterine bleeding in women with amenorrhea due to polycystic ovarian syndrome (PCOS). DESIGN: A comparative study. METHODS: Thirty-six patients with PCOS were classified according to body mass index into three weight groups, normal, overweight and obese. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were measured during amenorrhea and between days 3-5 after a chlormadinone (2 mg/day for 5 days) induced uterine bleed. Statistical analysis was performed with Wilcox-on test for paired groups and Mann-Whitney U-test for independent groups. RESULTS: Overall LH, FSH levels and the LH/FSH ratio fell significantly (P < 0.001, P < 0.01 and P < 0.001, respectively) after chlormadinone administration. The LH levels decreased in all three weight groups, the LH/FSH ratio only fell in those normal and overweight subjects, and FSH did not change in any group. When comparing the group with normal weight and those with overweight and obesity no hormonal differences were found. CONCLUSION: These results show that chlormadinone has an inhibitory effect predominantly over LH secretion which reduces the LH/FSH ratio, but this is independent of body weight.
Asunto(s)
Amenorrea/metabolismo , Índice de Masa Corporal , Acetato de Clormadinona/farmacología , Hormona Folículo Estimulante/metabolismo , Hormona Luteinizante/efectos de los fármacos , Síndrome del Ovario Poliquístico/metabolismo , Congéneres de la Progesterona/farmacología , Adolescente , Adulto , Amenorrea/etiología , Acetato de Clormadinona/administración & dosificación , Femenino , Humanos , Hormona Luteinizante/metabolismo , Síndrome del Ovario Poliquístico/complicaciones , Congéneres de la Progesterona/administración & dosificación , Factores de TiempoRESUMEN
1. The vast majority of bone mineralization in girls occurs by the middle of the second decade. 2. Premature bone demineralization occurs in women with hypothalamic dysfunction manifest as amenorrhea and oligomenorrhea, associated with athletics, dancing, and eating disorders. 3. In young women with amenorrhea associated with weight loss, BMD loss will be occurring soon after the amenorrhea develops. Treatment to prevent BMD loss or promote BMD accretion should begin soon, probably within 6 months after amenorrhea occurs. 4. Women who recover from anorexia nervosa at a young age (< 15 years of age) can have normal total body BMD, but regional (lumbar spine and femoral neck) BMD may remain low. The longer the anorexia nervosa persists, the less likely it is that the BMD will return to normal. Girls and women with anorexia nervosa need to be rehabilitated early in the disease to maximize BMD accretion. 5. Conjugated estrogen, in doses that improve bone mineralization in postmenopausal women and in combination with medroxyprogesterone, has not been shown to improve BMD in young women with hypothalamic amenorrhea. The role of orally administered medroxyprogesterone at a dose of 10 mg per day, 10 days per month, in improving BMD in teenage girls with hypothalamic amenorrhea or oligomenorrhea remains to be established. 6. Treatment with OCP may have a beneficial effect on BMD in young women with hypothalamic amenorrhea, but this has not been established in a double-masked, randomized, controlled trial. Doing a double-masked trial using OCP will be difficult because estrogen-deficient subjects treated with OCP will be likely to have menstrual bleeding, whereas those treated with placebo will not. In addition, the risk of pregnancy in a sexually active subject, who does not know whether she is receiving OCP, is too great for some subjects. 7. Osteoporosis is a major cause of morbidity and death. Peak bone mass is a major determinant of the risk of osteoporosis, and the second decade is the critical period of peak bone mass acquisition; thus providers of health care for adolescents need to understand the factors that affect bone mineralization during this period, and advise patients accordingly.
Asunto(s)
Amenorrea/tratamiento farmacológico , Calcificación Fisiológica , Calcio de la Dieta/administración & dosificación , Progestinas/uso terapéutico , Adolescente , Adulto , Amenorrea/etiología , Amenorrea/metabolismo , Amenorrea/fisiopatología , Desmineralización Ósea Patológica/etiología , Desmineralización Ósea Patológica/metabolismo , Desmineralización Ósea Patológica/terapia , Densidad Ósea/efectos de los fármacos , Calcificación Fisiológica/efectos de los fármacos , Calcificación Fisiológica/fisiología , Niño , Terapia Combinada , Quimioterapia Combinada , Terapia de Reemplazo de Estrógeno , Ejercicio Físico , Femenino , Humanos , Enfermedades Hipotalámicas/complicaciones , Oligomenorrea/tratamiento farmacológico , Oligomenorrea/etiología , Oligomenorrea/metabolismo , Oligomenorrea/fisiopatología , Osteoporosis/etiología , Osteoporosis/metabolismo , Osteoporosis/fisiopatología , Osteoporosis/terapia , Progestinas/farmacología , Pubertad/efectos de los fármacos , Pubertad/metabolismo , Factores de RiesgoRESUMEN
No Setor de Ginecologia Endocrina e Climaterio do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo foram estudadas 353 mulheres portadoras de amenorreia hipergonadotropica com o objetivo de analisar, retrospectivamente, os niveis alterados de gonadotropinas, e, tentar estabelecer correlacao entre possiveis padroes gonadotropicos e a etiopatogenia da amenorreia...
Asunto(s)
Humanos , Femenino , Adulto , Persona de Mediana Edad , Amenorrea/metabolismo , Gonadotropinas/metabolismo , Amenorrea/etiología , Hormona Folículo Estimulante/análisis , Hormona Luteinizante/análisisRESUMEN
The main side effect associated with the use of Norplant contraceptive implants is a disruption of the menstrual bleeding pattern. To explore the relationship between bleeding and hormonal changes, we analyzed the estradiol (E2) and progesterone (P) patterns that preceded bleeding episodes or that corresponded to periods of amenorrhea in 103 cycles observed among 82 women using Norplant subdermal implants. Five different bleeding patterns were defined: 'normal' (24-45 day cycles), oligomenorrhea (46-90 day cycles), amenorrhea (over 90 day cycles), irregular/frequent bleeding (less than 25 day cycles), and prolonged bleeding (continuous bleeding/spotting for more than 10 days). All 'normal' cycles were associated with a rise followed by a fall in E2 levels preceding bleeding. In half of the 'normal' cycles (28/54), a rise and fall of P was also observed. The same pattern was found in oligomenorrheic cycles, but only two of 12 cycles had a rise and fall of both E2 and P. None of the subjects with amenorrhea had luteal activity. Six of the nine amenorrheic cycles displayed persistently low E2 levels (below 75 pg/ml). The remaining three had a moderate elevation in E2 levels during the sampling period. Sixty percent of the subjects who showed irregular/frequent bleeding (15/25) had low E2 levels (less than 75 pg/ml), without luteal activity, and bleeding occurred without clear evidence of a further drop in E2 levels. In the remaining 40%, bleeding was preceded by a rise and drop of E2 without luteal activity, with the exception of one women, who exhibited a rise and fall of both E2 and P. Samples were obtained in only three subjects during continuous bleeding. One had low E2 levels, and the remaining two bled continuously, in spite of having E2 levels in the normal range. We conclude that ovarian hormones continue to influence endometrial shedding during the use of Norplant contraceptive implants.