Fisiologia do Sistema Endócrino Primeira parte: Diferenciação Sexual e puberdade humanas

1. Fisiologia do Sistema Endócrino Primeira parte: Diferenciação Sexual e puberdade humanas  Profa. Dra. Cristina Maria Henrique Pinto Profa. Adjunto do Depto. Ciências Fisiológicas-CCB-UFSC Como citar este documento: PINTO, Cristina Maria Henrique. Fisiologia Humana: Endocrinofisiologia. Disponível em: <http://www.cristina.prof.ufsc.br>.Acesso em: coloque a data aqui

2. ESQUEMAS PARA FACILITAR O ESTUDO E O ACOMPANHAMENTO DE MINHAS AULAS Bibliografia recomendada Livros-textos: “Fisiologia” Costanzo, 2007, 3ª Ed. (Ed. Elsevier) “Fundamentos de Fisiologia”, Berne et al, 2006, 4ª Ed.(Ed. Elsevier) “Berne & Levy: Fisiologia” Koeppen & Stanton, 2009, 6ª Ed. (Ed. Elsevier) “Fisiologia” Berne et al., 2004, 5ª Ed. (Ed. Elsevier) “Tratado de Fisiologia Médica” Guyton & Hall, 2006, 11ª Ed. (Ed. Elsevier) “Fisiologia” Aires, M. M., 2008, 3ª Ed. (Ed. Guanabara Koogan) “Fisiologia: texto e atlas” Despopoulos e Silbernagl, 2003 (Ed. Artmed)

3. AS FIGURAS AQUI UTILIZADAS FORAM RETIRADAS DE WEBSITES E, QUANDO POSSÍVEL, SÃO SEGUIDAS PELO ENDEREÇO NA INTERNET. PARA CONSULTA A TEXTOS E OUTROS RECURSOS ONLINE, VEJA EM: http://www.cristina.prof.ufsc.br PRESERVE O DIREITO AUTORAL CITANDO A FONTE.

4. Diferenciação sexual Até 7ª-8ª semanas de vida: Sexo gonádico indiferenciado sexo cromossômico 8ª semana sexo gonádico XY XX  sexo fenotípico Gene SRY/TDF  Diferenciação das gônadas no macho SRY: região determinante do sexo no cromossomo Y TDF: fator determinante testicular Griffin & Ojeda, 2000

5. A diferenciação sexual é determinada geneticamente XY A complex series of steps must occur in gonadal differentiation. A number of genes are critical to appropriate male genital development. SRY (sex determining region of the Y chromosome), a gene on the short arm of the Y chromosome, is a testis determining factor. The SOX9 gene is also important in male sexual differentiation. DAX1, an orphan member of a nuclear hormone receptor family located on the X chromosome, interacts with steroidogenic factor 1 (SF-1). Other genes involved in male gonadal differentiation include the tumor-suppressor gene WT1 (Wilms' tumor 1), and the Müllerian inhibiting substance gene (MIS) and its receptor, MIS-R. http://www.carolguze.com/text/442-6-sexual_differentiation.shtml

6. Genes ligados à diferenciação sexual  XX  XY http://www.mhhe.com/socscience/sex/common/ibank/set-3.htm

7. A diferenciação sexual é determinada geneticamente Hipótese sobre os genes reguladores XX XY Willians, 2003, pg. 864

8. XY sexo genotípico determinação do sexo gonádico SRY: região determinante do sexo no cromossomo Y TDF: fator determinante testicular http://anatomy.iupui.edu/courses/histo_D502/D502f04/lecture.f04/Malef04/MaleRepro.f03.html

9. XY  XY Gene SRY/TDF túb. seminíferos Diferenciação das gônadas do macho = testículos 8ª  9ªsem. Cél. de Sertoli fetais Cél. de Leydig fetais AMH (Hormônio Anti-Mülleriano) Testosterona sexo fenotípico Involução do Ducto de Müller DHT Evolução do Ducto de Wolff: orgãos sexuais internos Virilização da crista urogenital e da genitália externa

10. XY sexo genotípico sexo gonádico sexo fenotípico Normal sexual differentiation. A. Internal urogenital tract. B. External genitalia. Source: Harrison's Principles of Internal Medicine - 14th Edition http://www.gfmer.ch/Books/Reproductive_health/Human_sexual_differentiation.html

11. XY sexo genotípico sexo gonádico sexo fenotípico http://anatomy.iupui.edu/courses/histo_D502/D502f04/lecture.f04/Malef04/MaleRepro.f03.html

12. XY sexo genotípico sexo gonádico sexo fenotípico Fig. 5 texto: http://www.gfmer.ch/Books/Reproductive_health/Human_sexual_differentiation.html

13. Ausência da testosterona, de seus receptores ou mutações no AR (parcial ou total) Newborn genetic male (46XY) with complete androgen insensitivity syndrome and female external genitalia The gonads are bilateral intra-abdominal testes. The vagina is a short, blind-ending pouch, and the cervix, uterus, and fallopian tubes are absent due to testicular production of müllerian inhibitory substance. Nature Clinical Practice Urology (2004) 1, 38-43Current views on evaluation, management, and gender assignment of the intersex infant Caleb P Nelson* and John P Gearhart http://www.nature.com/ncpuro/journal/v1/n1/full/ncpuro0028.html An XY individual with androgen insensitivity syndrome http://www.dls.ym.edu.tw/lesson3/sex.htm The clinical findings that permit a presumptive diagnosis of AIS include the following: absence of extragenital abnormalities, two nondysplastic testes, absent or rudimentary müllerian structures (i.e., no fallopian tubes, uterus, or cervix) and the presence of a short vagina, undermasculinization of the external genitalia at birth and impaired spermatogenesis and/or somatic virilization at puberty (...) Veja mais em:http://www.geneclinics.org/profiles/androgen/details.html http://www.medhelp.org/www/ais/21_OVERVIEW.HTM#What

14. XY  XX  Gene SRY TDF Gônadas permanecem indiferenciadas Diferenciação das gônadas do macho = testículos 8ª  9ªsem. 11ª-12ª semanas: ausência de fatores genéticos masculinizantes (SRY) e presença de DAX1 - Diferenciação em ovários - Evolução do Ducto de Müller (involui Wolff) -Desenvolvimento das genitálias internas e externas Cél. de Sertoli fetais Cél. de Leydig fetais AMH (Hormônio Anti-Mülleriano) Testosterona Involução do Ducto de Müller DHT Evolução do Ducto de Wolff: orgãos sexuais internos Virilização da crista urogenital e da genitália externa

15. A diferenciação sexual é determinada geneticamente Hipótese sobre os genes reguladores XX XY Willians, 2003, pg. 864

16. XX sexo genotípico sexo gonádico sexo fenotípico Fig. 5 texto: http://www.gfmer.ch/Books/Reproductive_health/Human_sexual_differentiation.html

17. XX XY sexo genotípico sexo genotípico sexo gonádico sexo fenotípico Fig. 5 texto: http://www.gfmer.ch/Books/Reproductive_health/Human_sexual_differentiation.html

18. XY XX sexo genotípico sexo genotípico sexo gonádico sexo gonádico sexo fenotípico sexo fenotípico Normal sexual differentiation. A. Internal urogenital tract. B. External genitalia. Source: Harrison's Principles of Internal Medicine - 14th Edition http://www.gfmer.ch/Books/Reproductive_health/Human_sexual_differentiation.html

19.   Müller duct differentiation

20. Sobre diferenciação psicossexual : SALMON Study and learning materials on-line http://www.flyfishingdevon.co.uk/salmon/year1/psy128psychosexual_differentiation/sexdiff.htm

21. Aumento transitório da secreção de gonadotrofinas (LH e FSH), refletindo a secreção de GnRH/LHRH durante a gestação e alguns meses após o parto. Maturação do feedback inibitório dos esteróides gonadais Fig. 46-6 Pattern of gonadotropin secretion throughout life. Note transient peaks during gestation and early infancy and low levels thereafter in childhood. Women subsequently develop monthly cyclic bursts, with luteinizing hormone (LH) exceeding follicle-stimulating hormone (FSH); men do not. Both genders show increased gonadotropin production after age 50 years, with FSH exceeding LH.

22. Perfil de secreção de GnRH durante a gestação e após o parto Maturação do feedback inibitório dos esteróides gonadais (gestação) e diminuição dos esteróides placentários após o parto. year Ontogeny of the LHRH-pituitary-gonadal system before birth until after the onset of puberty in female rhesus monkeys (top) and in female humans (bottom). Days and months are used as the scale for the gestational period and after birth in monkeys, respectively, whereas weeks and years are used as the scale in humans. The age of events indicated in this figure is approximate. Terasawa e Fernandes, 2001

23. Durante a infância: baixa secreção de GnRH, LH e FSH Fig. 46-6 Pattern of gonadotropin secretion throughout life. Note transient peaks during gestation and early infancy and low levels thereafter in childhood. Women subsequently develop monthly cyclic bursts, with luteinizing hormone (LH) exceeding follicle-stimulating hormone (FSH); men do not. Both genders show increased gonadotropin production after age 50 years, with FSH exceeding LH.

24. Durante a infância: padrão de secreção de LH em 24 hs em indivíduo pre-púbere Fig. 46-7 LH secretion in childhood, puberty, and adult life. During puberty, the pattern of LH secretion becomes much more pulsatile. In addition, a nocturnal peak in LH is greatly amplified in early and middle puberty. This peak disappears when puberty is completed. Males and females both show these changes. As seen in the inset, nocturnal peaking is demonstrable even in childhood when a very sensitive LH assay is used.

25. Durante a infância: padrão de secreção de LH durante o sono em indivíduo pre-púbere Fig. 46-7 (...) LH nocturnal peaking is demonstrable even in childhood when a very sensitive LH assay is used.

26. Puberdade: aumento da secreção de GnRH e, consequentemente de LH e FSH Fig. 46-6 Pattern of gonadotropin secretion throughout life. Note transient peaks during gestation and early infancy and low levels thereafter in childhood. Women subsequently develop monthly cyclic bursts, with luteinizing hormone (LH) exceeding follicle-stimulating hormone (FSH); men do not. Both genders show increased gonadotropin production after age 50 years, with FSH exceeding LH.

27. Início da puberdade: a secreção de LH muda de padrão. começa a ocorrer um aumento dos pulsos de secreção de LH durante o sono Fig. 46-7 LH secretion in childhood, puberty. During puberty, the pattern of LH secretion becomes much more pulsatile. In addition, a nocturnal peak in LH is greatly amplified in early and middle puberty. This peak disappears when puberty is completed. Males and females both show these changes. een in the inset, nocturnal peaking is demonstrable even in childhood when a very sensitive LH assay is used.

28.   Padrões de secreções de LH/FSH na vida adulta fértil Fig. 46-6 Pattern of gonadotropin secretion throughout life. Note transient peaks during gestation and early infancy and low levels thereafter in childhood. Women subsequently develop monthly cyclic bursts, with luteinizing hormone (LH) exceeding follicle-stimulating hormone (FSH); men do not. Both genders show increased gonadotropin production after age 50 years, with FSH exceeding LH.

29. Vida adulta: desaparecimento dos picos noturnos de LH durante o sono Fig. 46-7 LH secretion in childhood, puberty, and adult life. During puberty, the pattern of LH secretion becomes much more pulsatile. In addition, a nocturnal peak in LH is greatly amplified in early and middle puberty. This peak disappears when puberty is completed. Males and females both show these changes. As seen in the inset, nocturnal peaking is demonstrable even in childhood when a very sensitive LH assay is used.

30. 2-Na puberdade aumenta a atividade dos nn. secretores de GnRH e secreções episódicas de gonadotrofinas aumentam com o tempo à medida que ocorre a maturação dos sinais integradores que passam a sofrer influências de sinais internos e externos. 1- Na instalação da puberdade, mecanismos neurais independentes de esteróides gonadais e, mais tarde, o feedback dos esteróides gonadais, desinibem e estimulam os neurônios secretores de GnRH 3-Os neurônios secretores de GnRH que projetam-se na EM secretam GnRH que estimula a secreção das gonadotrofinas (LH e FSH) e dos hormônios gonadais http://www.nature.com/neuro/journal/v7/n10/full/nn1326.htmlThe neural basis of puberty and adolescence Cheryl L Sisk & Douglas L Foster, Nature Neuroscience  7, 1040 - 1047 (2004) 27 September 2004

31. 2-Na puberdade aumenta a atividade dos nn. secretores de GnRH e secreções episódicas de gonadotrofinas aumentam com o tempo à medida que ocorre a maturação dos sinais integradores que passam a sofrer influências de sinais internos e externos. 1- Na instalação da puberdade, mecanismos neurais independentes de esteróides gonadais e, mais tarde, o feedback dos esteróides gonadais, desinibem e estimulam os neurônios secretores de GnRH 3-Os neurônios secretores de GnRH que projetam-se na EM secretam GnRH que estimula a secreção das gonadotrofinas (LH e FSH) e dos hormônios gonadais 4-Os esteróides sexuais promovem as características sexuais secundárias nos tecidos periféricos, regulam a secreção de GnRH por feedback e agem no SNC facilitando os comportamentos sexuais e sociais. http://www.nature.com/neuro/journal/v7/n10/full/nn1326.htmlThe neural basis of puberty and adolescence Cheryl L Sisk & Douglas L Foster, Nature Neuroscience  7, 1040 - 1047 (2004) 27 September 2004

32. Neuroendocrinologia da Reprodução

33. Neuroendocrinologia da Reprodução

35. Final da infância: Surgimento de picos noturnos de secreção de LH (Hormônio Luteinizante) pela adenohipófise GnRH: hormônio liberador de gonadotrofinas, LHRH; Gonadotrofinas: LH (hormônio luteinizante) e FSH (hormônio folículo-estimulante)

36. Final da infância: surgimento de picos noturnos de LH  GnRH  GnRH FSHe LH • LH e  FSH GnRH: hormônio liberador de gonadotrofinas, LHRH; Gonadotrofinas: LH (hormônio luteinizante) e FSH (hormônio folículo-estimulante)

37. Final da infância: surgimento de picos noturnos de LH  GnRH  GnRH FSHe LH • LH e  FSH GnRH: hormônio liberador de gonadotrofinas, LHRH; Gonadotrofinas: LH (hormônio luteinizante) e FSH (hormônio folículo-estimulante)

38. Primeira manifestação da PUBERDADE: amplificação dos picos diurnos de LH GnRH: hormônio liberador de gonadotrofinas, LHRH; Gonadotrofinas: LH (hormônio luteinizante) e FSH (hormônio folículo-estimulante)

39. A secreção de LH (e GnRH) é independente da presença das gônadas

40. Primeira manifestação da PUBERDADE: amplificação dos picos diurnos de LH Ativação da secreção de GnRH hipotalâmico por perda da restrição inibitória da circuitaria do SNC sobre a atividade dos neurônios GnRHérgicos  GnRH  LH  FSH

41. PUBERDADE: secreção deLHe deFSH  GnRH  GnRH FSH e LH • LH e  FSH GnRH: hormônio liberador de gonadotrofinas, LHRH; Gonadotrofinas: LH (hormônio luteinizante) e FSH (hormônio folículo-estimulante)

42. http://www.gfmer.ch/Medical_education_En/PGC_RH_2004/Pdf/Puberty.pdfhttp://www.gfmer.ch/Medical_education_En/PGC_RH_2004/Pdf/Puberty.pdf

43. Instalação da puberdade Infância Influências inibitórias Influências inibitórias nn. GnRH nn. GnRH Influências excitatórias Influências excitatórias (Conn e Freeman, 2000)

44. Fig. 46-8 Development of pubertal gonadotropin secretion. In childhood a dominant negative tone is exerted on GnRH neurons by GABA (γ-aminobutyric acid) neurons, supplemented by negative input from NPY (neuropeptide Y) neurons. During puberty, GABA tone diminishes permitting a dominant positive tone from glutamate neurons. A decrease in nocturnal melatonin and a decrease in NPY tone wrought by an increase in leptin also help relieve the prepubertal suppression of GnRH. Negative input by endorphins and negative feedback by T (testosterone) and E2 (estradiol) are barely present before puberty but are greatly augmented by puberty. Berne et al, 2004

45. Fig. 46-8 Development of pubertal gonadotropin secretion. In childhood a dominant negative tone is exerted on GnRH neurons by GABA (γ-aminobutyric acid) neurons, supplemented by negative input from NPY (neuropeptide Y) neurons. During puberty, GABA tone diminishes permitting a dominant positive tone from glutamate neurons. A decrease in nocturnal melatonin and a decrease in NPY tone wrought by an increase in leptin also help relieve the prepubertal suppression of GnRH. Negative input by endorphins and negative feedback by T (testosterone) and E2 (estradiol) are barely present before puberty but are greatly augmented by puberty. Berne et al, 2004

46. Sinais metabólicos também parecem ser importantes mas não seriam determinantes Fig. 46-8 Development of pubertal gonadotropin secretion. In childhood a dominant negative tone is exerted on GnRH neurons by GABA (γ-aminobutyric acid) neurons, supplemented by negative input from NPY (neuropeptide Y) neurons. During puberty, GABA tone diminishes permitting a dominant positive tone from glutamate neurons. A decrease in nocturnal melatonin and a decrease in NPY tone wrought by an increase in leptin also help relieve the prepubertal suppression of GnRH. Negative input by endorphins and negative feedback by T (testosterone) and E2 (estradiol) are barely present before puberty but are greatly augmented by puberty. Berne et al, 2004

47. Influências propostas para a regulação da secreção de GnRH em rato + GnRH esteróides gonadais Neuronal cell populations within the GnRH network implicated in transmitting estrogen input to GnRH neurons in the rat. This may be direct or indirect on the GnRH neuron and involve cell body or terminal levels of regulation. Note that the neurochemical identity of estrogen-receptive neurons within the GnRH network is not fully established. Neurons with black nuclei express nuclear ERs. An estrogen-receptive neuronal population in the AVPv is hypothesized to project to, and coordinate, neuronal activity within the arcuate nucleus. AVPv/preoptic = núcleo pré-óptico medial de rato Herbison, 1998

49. Interações dos hormônios sexuais com hormônios reguladores do crescimento (GH e somatomedianas) Fig. 46-9 Interaction between growth and reproduction. The products of the GH (growth hormone)-IGF-1 (insulin growth factor-1) axis stimulate reproductive function in the GnRH (gonadotropin-releasing hormone)-LH (luteinizing hormone), FSH (follicle-stimulating hormone)-T (testosterone) and E2 (estradiol) axis. Lkewise T and E2 stimulate GH secretion and growth. (From Hull KL: J Endocrinol 172:1, 2002.)

50. PUBERTY IN NONHUMAN FEMALE PRIMATES. Figure 2. Schematic illustration of postnatal changes in LHRH release and neurotransmitter events that occur in the hypothalamus in association with puberty in nonhuman female primates. The LHRH neurosecretory system appears to be active during the infantile period, but is suppressed by an inhibitory mechanism comprising GABA neurons. At the onset of puberty, a reduction in GABA inhibition and a subsequent increase in glutamate excitation of LHRH neurons result in the pubertal increase in the pulse frequency, pulse amplitude, and baseline levels of LHRH, which trigger puberty. Furthermore, a higher nocturnal level of LHRH release, shown by hatched bars, becomes particularly prominent. After the onset of puberty, other stimulatory neurotransmitters such as NPY and NE take part in control of LHRH neurons, resulting in further increases in the pulse amplitude and baseline level of LHRH release, until the time of first ovulation. The nocturnal increase in LHRH release and LHRH pulse amplitude are reduced to the adult level, perhaps due to participation of inhibitory neurotransmitters, such as opioids. Stippled bars indicate morning levels of LHRH. In males the LHRH neurosecretory system is fully mature during the infantile period, but is suppressed completely during the juvenile period. Recently, it has been hypothesized that NPY is an inhibitory neurotransmitter before puberty in males. Terasawa e Fernandes, 2001 http://edrv.endojournals.org/cgi/content/full/22/1/111#F1