Como se inicia la pubertad Que son las alteraciones menstruales Que es la leptina Que son los trastornos alimentarios Que relación tiene la leptina con los trastornos alimentarios Que relación tiene la leptina con las alteraciones menstruales.
NORMAL AND ABNORMAL PUBERTY Lucia Ghizzoni, Ghizzoni, MD, Maria E. Street MD, Maddalena Marchesi MD, and Vera Raggi MD Updated: Updated: March 5, 2007
Hypothalamic KiSSKiSS-1 system also plays an essential role in relaying the negative feedback feedback input of sex steroids onto GnRH neurons. Indeed, both in male and female rats, bilateral bilateral gonadectomy evoked a consistent increase in KiSSKiSS-1 mRNA at the hypothalamus. More recently, some studies added further further refinement to our knowledge of the role of kisspeptin in the feedback control of gonadotropins. These These studies demonstrated that negative regulation of hypothalamic KiSSKiSS-1 gene expression by estrogen appears to be restricted to the arcuate arcuate nucleus (Arc), an area classically recognized as pivotal for negative feedback of sex steroids. steroids. In contrast, at the anteroventral periventricular nucleus (AVPN), KiSSKiSS-1 mRNA decreased after gonadectomy and increased after sex steroid steroid replacement (43,44). Considering that the AVPN has been involved in mediating the positive feedback effects of estrogen upon GnRH and LH surges, KiSSKiSS-1 neurons might be involved also in generation of the prepre-ovulatory gonadotropin surge, via positive regulation of GnRH secretion. Thus, Thus, KiSSKiSS-1 system is an essential downstream element in the negative and (probably) positive feedback loops controlling controlling gonadotropin secretion (45). Besides feedback control, compelling evidence indicates that hypothalamic hypothalamic KiSSKiSS-1 may participate in delivering information regarding the nutritional status of the organism to GnRHGnRH- neurons, thereby contributing to the link between energy stores and fertility. In rats LH responses to kisspeptin in vivo and GnRH responses in vitro were significantly augmented in fasting conditions, suggesting that a decrease in central central KiSSKiSS-1 tone occurs during negative energy balance, which may in turn cause inhibition of the gonadotropic axis and sensitization to the effects of exogenous kisspeptin (46). Repeated administration of kisspeptin in a model model of underunder-nutrition of immature female rats was sufficient to restore vaginal opening (as external index of puberty) puberty) in a significant number of animals and induced robust gonadotropin and estrogen responses in all rats treated with with kisspeptin. Since the permissive actions of leptin on the reproductive axis are mediated through modulation of GnRH secretion, and GnRH neurons do not express leptin receptors, (47) kisspeptins can be considered plausible plausible candidates for ultimately conveying metabolic cues, likely signalled via peripheral hormones such as leptin, onto GnRH neurons. Several key aspects of the physiology of this system remain to be be clarified. For instance, the nature and hierarchical position of KiSSKiSS-1 neurons within the complex network controlling the GnRH pulse generator are yet to be completely defined. It was recently proposed that KiSSKiSS-1 and GPR54 are subordinate genes, under the control of upstream regulators, whose protein products operate as as transtrans-synaptical regulators of GnRH neurons (48)
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GPR54 and KiSSKiSS-1: Role in the regulation of puberty and reproduction
Wendy Kuohung1, Kuohung1, 2 and Ursula B. Kaiser2 (1) Department of Obstetrics and Gynecology, Gynecology, Boston University School of Medicine, Boston, MA 02118, 02118, USA(2) Division of Endocrinology, Endocrinology, Diabetes, and Hypertension, Hypertension, Brigham and Women’s Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115, USA Published online: 6 January 2007
Abstract The finding of inactivating mutations in GPR54 in IHH patients and the lack of reproductive maturation of the GPR54 null mouse have uncovered a previously unrecognized role for GPR54 and KiSSKiSS-1 in the physiologic regulation of puberty and reproduction. reproduction. This newly identified function for GPR54 and its cognate ligand, ligand, kisspeptin, kisspeptin, has led to additional studies that have localized GPR54 and KiSSKiSS-1 mRNA in the hypothalamus, hypothalamus, colocalized GPR54 in GnRH neurons, neurons, demonstrated GnRHGnRH-dependent activation of LH and FSH release by kisspeptin, kisspeptin, and shown increased hypothalamic KiSSKiSS-1 and GPR54 mRNA levels at the time of puberty. puberty. Taken together, together, these findings establish the role of the kisspeptinkisspeptin-GPR54 system in the stimulation of GnRH neurons during puberty. puberty. The mechanisms by which kisspeptin activates GnRH release, release, as well as the trigger for this pathway at the onset of puberty, puberty, are yet to be elucidated. elucidated. In the future, future, modulators of GPR54 activity, activity, including kisspeptin, kisspeptin, may prove valuable in clinical applications in the fields of both cancer therapy and reproductive medicine
KiSSKiSS-1 neurones are direct targets for leptin in the ob/ ob/ob mouse. mouse. JT, JT, Acohido BV, BV, Clifton DK, DK, Steiner RA. RA.
Department of Physiology and Biophysics, Biophysics, School of Medicine, University of Washington, Seattle, Seattle, 9819598195-7290, USA. Abstract Leptin is an adipocyteadipocyte-derived hormone that acts on the hypothalamus to influence feeding, feeding, metabolism and reproduction, reproduction, but the cellular and molecular targets for the action of leptin in the brain have yet to be fully elucidated. elucidated. Kisspeptins are encoded by the Kiss1 gene, which is expressed in the hypothalamus and has been implicated in the neuroendocrine regulation of gonadotrophingonadotrophin-releasing hormone secretion. secretion. We tested the hypothesis that kisspeptinkisspeptin-expressing neurones are targets for leptin. leptin. First, First, we examined whether leptin regulates the expression of Kiss1 by comparing levels of KiSSKiSS-1 mRNA in the arcuate nucleus among groups of mice having different circulating levels of leptin: leptin: (i) wildwild-type (WT); (ii (ii)) leptinleptin-deficient ob/ ob/ob; ob; and (iii) iii) ob/ ob/ob mice treated with leptin. leptin. All mice were castrated to control for endogenous concentrations of gonadal steroids. steroids. KiSSKiSS-1 mRNA was significantly reduced in ob/ ob/ob compared to WT mice and levels of KiSSKiSS-1 mRNA in ob/ ob/ob mice treated with leptin were increased, increased, but not fully restored to that found in WT animals. animals. Second, Second, we performed doubledouble-label in situ hybridisation for KiSSKiSS-1 mRNA and the leptin receptor (Ob (Ob--Rb) Rb) mRNA and found that almost oneone-half (approximately 40%) of KiSSKiSS-1 mRNAmRNA-expressing cells in the arcuate nucleus expressed ObOb-Rb mRNA. mRNA. These results demonstrate that KiSSKiSS-1 neurones are direct targets for regulation by leptin and suggest that the reproductive deficits associated with leptinleptin-deficient states may be attributable, attributable, in part, part, to diminished expression of Kiss1. Neuroendocrinol. Neuroendocrinol. 2006 Apr;18(4):298 Apr;18(4):298--303.
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Regulation of Hypothalamic Genes by Metabolic Factors: Factors: Analyses Using Mouse Models and a Cell Line Raul M. Luque, Rhonda D. Kineman and Manuel TenaTena-Sempere
Section of Endocrinology, Endocrinology, Diabetes, and Metabolism (R.M.L., R.M.L., R.D.K.), R.D.K.), Department of Medicine, University of Illinois at Chicago, Chicago, Chicago, Illinois 60607; Research and Development Division (R.M.L., R.M.L., R.D.K.), R.D.K.), Jesse Brown Veterans Affairs Medical Center, Center, Chicago, Illinois 60612; Department of Cell
BioloS.),Instituto BioloS.),Instituto Salud Carlos III, 28029 Madrid, Spain
It is well established that reproductive function is metabolically gated. gated. However, However, the mechanisms whereby energy stores and metabolic cues influence fertility are yet to be completely deciphered. deciphered. Recently, Recently, the hypothalamic KiSSKiSS-1/GPR54 system has emerged as a fundamental regulator of the gonadotropic axis, axis, which conveys the modulatory actions of sex steroids to GnRH neurons. neurons. Evidence is also mounting that KiSSKiSS-1 neurons may also represent the link between systemic metabolic signals and central control of reproduction. reproduction. To further explore this possibility, possibility, we examined the impact of changes in energy status and key metabolic regulators on the hypothalamic expression of KiSSKiSS-1 and GPR54 genes, using different mouse models and the hypothalamic cell line N6. TimeTime-course analysis of the effects of shortshort-term fasting revealed a rapid (12(12- and 2424-h) decline in KiSSKiSS-1 and GPR54 mRNA levels, levels, which preceded that of GnRH (48 h). In contrast, contrast, dietdiet-induced obesity or obesity associated with leptin deficiency (ob/ ob/ob vs. vs. wildwildtype mice) mice) failed to induce overt changes in hypothalamic expression of KiSSKiSS-1 and GPR54 genes. However, However, leptin infusion of ob/ ob/ob mice evoked a significant increase in KiSSKiSS-1 and GPR54 mRNA levels compared with pairpair-fed controls. controls. Moreover, Moreover, leptin, leptin, but not insulin or IGFIGF-I, stimulated KiSSKiSS-1 mRNA expression in the mouse hypothalamic cell line N6. In addition, addition, neuropeptide Y (NPY) null mice showed decreased KiSSKiSS-1 mRNA levels at the hypothalamus, hypothalamus, whereas exposure to NPY increased expression of KiSSKiSS-1 in hypothalamic N6 cells. cells. In sum, sum, our present data further characterize the functional relevance and putative key mediators (such as leptin and NPY) of the metabolic regulation of the hypothalamic KiSSKiSS-1 system in the mouse. mouse. Endocrinology, Endocrinology, doi:10.1210/en.2007 doi:10.1210/en.2007--0500 Endocrinology Vol. 148, No. 10 46014601-4611
Como se inicia la pubertad
3
Como se inicia la pubertad Que son las alteraciones menstruales Que son los trastornos alimentarios Que es la leptina Que relación tiene la leptina con los trastornos alimentarios Que relación tiene la leptina con las alteraciones menstruales.
Alteraciones del Ciclo en adolescentes Evolución espontánea
Postmenarca: 49% regulares 51% irregulares
3 años
57% se regularizan 43% no se regularizan (23%
del total)
Mendez Ribas J. Maria Tesis 1982
4
Clasificación trastornos menstruales complejos
simples Inmadurez del eje HipotalamoHipotalamo-HipofisoHipofisoovarico Post menarca Carácter transitorio Sin síntomas endocrinológicos
Comienzan en adolescencia Repercusiones en fertilidad. Repercusiones metabólicas. metabólicas.
Patología que comienza en la adolescencia Anovulaciòn crónica Ovarios hiperandrogènicos Amenorrea por perdida de peso Falla ovárica precoz Hiperprolactinema
ESTERILIDAD
5
Amenorrea
Nivel de gonadotrofinas •Hipergonadotrófica •Hipogonadotrófica •Normogonadotrófica
Alteraciones menstruales Disfunción Hipotámo-hipófiso-ovárica Patología orgánica pelviana Patología sistémica Disfunción endócrina extragenital: Tiroides Suprarrenal Prolactina
6
Como se inicia la pubertad Que son las alteraciones menstruales Que son los trastornos alimentarios Que es la leptina Que relación tiene la leptina con los trastornos alimentarios Que relación tiene la leptina con las alteraciones menstruales
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA TRASTORNOS ALIMENTARIOS
SICOLÓGICO
BIOLÓGICO
ADOLESCENCIA
SOCIAL
AMENORREA OLIGOMENORREA
7
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA
Trastornos alimentarios
ANOREXIA NERVIOSA
T.A.N.E. BULIMIA NERVIOSA
D.S.M. IV (Academia Americana de Psiquiatria) 1994
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA Criterios diagnósticos para Anorexia y Bulimia nerviosa (DSM-IV) * Anorexia Nerviosa
• Rechazo a mantener un peso corporal normal o por encima del mínimo aconsejable. • Miedo a ganar peso o engordar, aún estando por debajo de su peso normal. • Distorsión en la percepción de peso e imagen corporal. • Amenorrea (en postmenárquicas).
8
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA Criterios diagnósticos para Anorexia y Bulimia nerviosa (DSM-IV) * Bulimia Nerviosa • Episodios recurrentes de atracón. • Comportamiento recurrente e inapropiado compensatorio para prevenir la ganancia ponderal, como vómitos autoinducidos, ayuno o ejercicio excesivo, uso de laxantes, diuréticos u otra medicación. • Los atracones y el comportamiento compensatorios inapropiados, ocurren ambos, al menos dos veces por semana durante tres meses. • La autoestima está indebidamente influenciada por la figura corporal y el peso. • Está ausente el cuadro de anorexia nerviosa.
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA Tipos específicos de Anorexia y Bulimia nerviosa (DSM-IV)
Purgativo: La persona se ve implicada en vómitos autoinducidos, uso de laxantes y/o diuréticos como comportamientos compensatorios. No purgativo: La persona utiliza otros comportamientos compensatorios inadecuados, como períodos de ayuno y/o ejercicio excesivo.
9
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA
Anorexia Nerviosa
Bulimia Nerviosa
Como se inicia la pubertad Que son las alteraciones menstruales Que son los trastornos alimentarios Que es la leptina Que relación tiene la leptina con los trastornos alimentarios Que relación tiene la leptina con las alteraciones menstruales
10
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA
LEPTINA
Shina et. al ., J Clin. Invest 1996 ; 97:1344-1347
LEPTINA Corteza cerebral Sistema límbico
Tronco del encéfalo
Barrera hematoencefálica
Y Y Hipotálamo Y Angiogénesis / Fibrogénesis Inmunidad / Inflamación
Ingesta Gasto energético Metabolismo
Reproducción
Y
Absorción intestinal Ob-R
Funciones neuroendócrinas
Leptina Lipólisis/Otras
Modificado Friedman Halaas, 1998
11
LEPTINA EFECTO CENTRAL Hipotálamo
•
NPY
• GnRH
Tejido adiposo (liberación de leptina)
VN: 6.9/12ng./ml.
EFECTO PERIFERICO • • • •
Actividad física Pérdida de calor Consumo energético Depósitos de grasa
EJE HIPOTALAMO-HIPOFISO-ADIPOSO
Relleno corporal Aislante térmico Órgano endócrino Vieytez, Marquez Lopez Mato Psiconeuroinmonoendrocrinología 2004
12
Depósitos grasos
LEPTINA
GASTO ENERGÉTICO
EJE ADRENAL
FUNCIÓN REPRODUCTIVA Flier: J. Clin. Endocrinol. Metab. (1998)
Como se inicia la pubertad Que son las alteraciones menstruales Que son los trastornos alimentarios Que es la leptina Que relación tiene la leptina con los trastornos alimentarios Que relación tiene la leptina con las alteraciones menstruales
13
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA Eje hipotálamo-hipofiso - gonadal Hipófisis Hormona Folículo Estimulante (FHS) Hormona Luteinizante (HL)
..
Hipotálamo Hormona liberadora de Gonadotrofina (GnRH) Leptina < 3ng. / ml.
Ovarios
Masa corporal crítica< 17 %
Estrógenos y Progesterona
AMENORREA
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA Pacientes y métodos
• Tipo de estudio: transversal • n= 52 pacientes • Rango: 12 a 22 años • Antecedentes de ciclos menstruales regulares previos • No embarazadas • Reclutamiento 2000/2001
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TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA Configuración de pacientes Grupo Anorexia Nerviosa : (AN) n:15 Grupo Bulimia Nerviosa: (BN) n: 15 Departamento de Psicopatología y Trastornos Alimentarios Hospital Nacional de Clínicas U.N.C. Grupo Control: (GC) n: 10 Consultorio de Adolescencia II Cátedra de Clínica Ginecológica, Hospital Universitario de Maternidad y Neonatología, U.N.C. Dosajes Hormonales : Laboratorio de R.I.A. Hosp. Nacional de Clínicas (Dra. Bergoglio)
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA 2. Evaluaciones hormonales: Quimioluminiscencia
• Leptina, FSH , LH y TSH (UI./L.) • Estradiol (pg./ml.) • Prolactina (ng./ml.) • Testosterona (ng./dl.) • Insulina (mUI/L)
15
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA 1.Leptina y composición corporal ANORÉXICAS Raíz cuadrada cuadrada de de Leptina Leptina (ng/ml) (ng/ml) Raíz
1,00 1,00 3,0 9,00 9,00 8,00 2,8 8,00 7,00 7,00 2,5 6,00 6,00 2,3 5,00 5,00 2,0 4,00 4,00 1,8 3,00 3,00 1,5
2,00 2,00
1,3 1,0 1,00 1,00 ,8 ,5 0,25 0,25 10 11
12
13
14
15
16
(p= 0.016) 0.016)
3,5
(p= (p= 0.017) 0.017)
3,3
17
18
19
3,3
10,00 10,00 3,0 9,00 9,00 8,00 8,00 2,8 7,00 7,00 2,5 6,00 6,00 2,3 5,00 5,00 2,0 4,00 4,00 1,8 3,00 3,00 1,5
2,00 2,00
1,3 1,0 1,00 1,00 ,8 ,5 0,25 0,25 0 2
20
4
6
8
10
Indice de Masa Corporal (Kg/m2)
12
14
16
18
20
22
24
26 28
30
Grasa Grasa Corporal Corporal (%) (%)
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA
Raíz cuadrada cuadrada de Leptina Leptina (ng/ml) Raíz
2. Leptina y Hormonas Sexuales Raíz cuadrada de Leptina (ng/ml)
Raíz cuadrada de Leptina (ng/ml)
3,5
77
7
66
6 30,00
pp == 0,228 0,228
5 20,00 4
10,00
33
8,00
pp == 0,002 0,002
Grupos Grupos
6,00 4,00
2
Control Control
2,00 1
Bulimia Bulimia
1,00
Min. Min. normal normal de de FSH FSH
Anorexia Anorexia
0 0
1
pp == 0,028 0,028 20,00
pp == 0,143 0,143
44 15,00
15,00
3
30,00
55
pp == 0,725 0,725
2
3
4
5
6
7
8
9
10
FSH FSH (UI/L) (UI/L)
11
12
13
14
10,00
pp == 0,010 0,010
8,00
Grupos Grupos
6,00
Control Control
22 4,00
Bulimia Bulimia
2,00 11 1,00
Anorexia Anorexia Min. Min. normal normal de de LH LH
00 ,5 ,5
1,0 1,0 1,0
2,0
4,0
1,5 1,5
2,0 2,0
6,0 2,5 2,5
8,0
10,0 3,0 3,0
15,0 3,5 3,5
4,0 4,0
Raíz cuadrada de LH (UI/L)
16
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA
Leptina (ng/ml) (ng/ml) Leptina
3. Concentración sérica de Leptina 44 44 42 42 40 40 38 38 36 36 34 34 32 32 30 30 28 28 26 26 24 24 22 22 20 20 18 18 16 16 14 14 12 12 10 10 88 66 44 22 00 N=
(p= (p= 0.01) 0.01)
(p= (p= 0.01) 0.01)
Med Med == 13,0 13,0
Med Med == 12,0 12,0
RIC RIC == 9,25-21,3 9,25-21,3
RIC RIC == 9,5-29,0 9,5-29,0
(p= (p= 1.00) 1.00)
Med Med == 3,80 3,80 RIC RIC == 2,65-7,15 2,65-7,15
N=
15
15
10
Anorexia
Bulimia
Control
Grupos de Estudio
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA 4. Características Antropométricas
30,0 30,0 28,0 28,0 26,0 26,0 24,0 24,0 22,0 22,0 20,0 20,0 18,0 18,0 16,0 16,0 14,0 14,0 12,0 12,0 10,0 10,0 8,0 8,0 6,0 6,0 4,0 4,0 2,0 2,0 0,0 0,0
40,0 40,0
21,7 21,7
20,5 20,5 15,7 15,7
Bulimia
Control
Anorexia
Grasa Corporal Corporal (%) (%) Grasa
Indice de de Masa Masa Corporal Corporal (Kg/m2) (Kg/m2) Indice
45,0 45,0
35,0 35,0 30,0 30,0
30,7 30,7 28,8 28,8
25,0 25,0 15,2 15,2
20,0 20,0 15,0 15,0 10,0 10,0
Bulimia
Control
Anorexia
5,0 5,0 0,0 0,0
Las Las barras barras en en gris gris representan representan la la media media En En rojo rojo el el desvío desvío estandar estandar
Las Las barras barras en en gris gris representan representan la la media media En En rojo rojo el el desvío desvío estandar estandar
17
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA Conclusiones
•Los niveles plasmáticos de Leptina fueron significativamente bajos en pacientes con AN, lo que refleja la estrecha relación entre el nivel de Leptina con la composición corporal y el IMC, no observándose variaciones en GC y BN.
TRASTORNOS ALIMENTARIOS, ALTERACIONES MENSTRUALES Y LEPTINA Conclusiones • El descenso de los niveles plasmáticos de Leptina (
