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DETERMINAREA SEXULUI Genes involved in the creation of undifferentiated gonad WT1 – gene : its abnormality is associated with failure of gonadal differentiation.

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Presentation on theme: "DETERMINAREA SEXULUI Genes involved in the creation of undifferentiated gonad WT1 – gene : its abnormality is associated with failure of gonadal differentiation."— Presentation transcript:

1 DETERMINAREA SEXULUI Genes involved in the creation of undifferentiated gonad WT1 – gene : its abnormality is associated with failure of gonadal differentiation Deny-Drash syndrome: - failure in gonadal differentiation - nephropaty - Wilms’tumour Frasier’s syndrome: - failure of gonadala differentiation - gonadoblastoma WAGR syndrome: - aniridia - genital abnormalities, mental retardation Hiort O., Holterus P-M: The mollecular bases of male sexual diffrentiation. Eur.J.Endocrinol. 2000, v. 142,

2 DETERMINAREA SEXULUI Genes involved in the creation of undifferentiated gonad LIM-1 gene: homozygous deletion: failure of development of both gonads and kidney In humans renal and gonadal abnormalities associated with brain abnormalities were reported FTZ-1-F1 – gene for SF-1 – steroidogenic factor 1 encodes a nuclear orphan receptor Its mRNA is found in the genital ridge, adrenals and hypothalamus Its deletion in mice determines failure of developing gonads, adrenals and hypothalamus Roles of SF-1: gonadal differentiation, adrenal and hypothalamus differentiation, regulates enzyimes involved in steroidogenesis, regulates transcription of anti-Mullerian hormone (AMH) Hiort O., Holterus P-M: The mollecular bases of male sexual diffrentiation. Eur.J.Endocrinol. 2000, v. 142,

3 DETERMINAREA SEXULUI Testis determining factor (TDF) = SRY – sex-determining region of the Y chromosome A single exon gene that: - binds to the promoter of AMH-gene induces the expression of AMH and prevents the formation of Mullerian ducts - genetic engineering: female xx embrios transfected with sry develop a normal male phenotype SRY mutations are associated with complete sex reversal in 46, xy individuals SRY mutations were described in true hermaphroditism with both testicular and ovarian tissues development Hiort O., Holterus P-M: The mollecular bases of male sexual diffrentiation. Eur.J.Endocrinol. 2000, v. 142,

4 DETERMINAREA SEXULUI Autosomal genes involved in male sex determination SOX-9 (SRY-box related) transcribed following SRY expression in male genital structures. It is also an activator of the type 2 collagen gene. Defects in SOX-9 determine sex reversal in 46.xy individuals and skeletal malformations known as campomelic dysplasia Chromosome 10q: its terminal deletion is associated with genital malformations and mental retardation Hiort O., Holterus P-M: The molecular bases of male sexual differentiation. Eur.J.Endocrinol. 2000, v. 142,

5 DETERMINAREA SEXULUI DAX-1 : dosage sensitive sex reversal locus-adrenal hypoplasia congenita-critical region on the X chromosome, gene-1. (Xp21) DAX-1 gene is expressed during ovarian development but is suspended during testicular formation. DAX-1 is critical for ovarian development DAX-1 gene is repressed by SRY during testicular development DAX-1 gene duplication results in impaired testicular formation and sex reversal Mutations in DAX-1 gene diminishing gene activity determine congenital adrenal hypopplasia and hypogonadotropic hypogonadism Hiort O., Holterus P-M: The mollecular bases of male sexual diffrentiation. Eur.J.Endocrinol. 2000, v. 142,

6 DIFERENTIEREA SEXULUI
Sertoli AMH TESTICUL DMRT-1, -2 SOX 9 SRY Leydig - testosteron WT-1 LIM-1 GONADA BIPOTENTIALA MEZODERM SF-1 DAX 1 ESTROGENI, PROGESTERON OVAR

7 DIFERENTIEREA SEXULUI

8 Testiculul repere anatomice

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11 TESTICULUL ANATOMIE

12 TESTICULUL HISTOLOGIE

13 TESTICULUL

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15 SPERMIOGENEZA

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19 CELULA SERTOLI

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25 TESTICULUL Defect de P450 –aromataza la barbat Cromozom 15 q21.1
Faustini-Fustini Marco: Eur.J. Endocrinol, 1999, 140,

26 Clinical features in congenital oestrogen deficiency
Female Male Fetal life Mother’s transient viriliztion during seond half of pregnancy External genitalia at birth Amiguos genitalia Prader IV-V with a greatly enlarged phallic-like structure-clitoromegaly, complete fusion of posterior labioscrotal folds, and a single meatus at the base of the phallic structure Normal maleexternal genitalia Childhood Delayed bone age Unremarcable Puberty Absent breast development, primary amenorhoea, further enlargement of cclitoris; virilization and normal development of axillary and pubic hair, absent growth spurt, delayed bone age Normal pubertal development, delayed bone age, normal growth spurt? adulthood Severe estrogen deficiecy, virilization, multicystic ovaries, osteoporosis, inferility, unfused epiphyses?if untreated, tall stature Gigantism (stature >3 SD) and continuing linear growth in adulthood; unfesed apiphyses, eunuchoid skeleton, bilateral genu valgum, osteoporosis, infertility

27 Congenital oestrogen deficiency

28 TESTICULUL

29 TESTICULUL

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31 TESTICULUL

32 TESTICULUL

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37 TESTICULUL

38 EFECTELE ANDROGENILOR - prenatal
TESURI TINTA ANDROGENI IMPLICATI ACTIUNE REZULTATE CANALELE WOLF T stimulare Dezvoltarea OGI, epididim, canale deferente SINUS URO-GENITAL DHT Dezvoltarea tuberculului genital, a glandului, fuziunea plicilor uretrale si genitale cu formarea scrotului, dezvoltarea prostatei HIPOTALAMUS FETAL T aromatizat in Estradiol Dezvoltarea sexului neuro-hormonal masculin cu secretie continua de LH-RH ( lunile IV-VI) SISTEM NERVOS CENTRAL T, DHT, E2 Sexualizarea neuro-comportamentala cu creerea unui promordiu de sex masculin care va fi dezvoltat educational si stimulat prin androgeni la pubertate si in viata adulta

39 EFECTELE ANDROGENILOR – neonatal, pubertar
TESURI TINTA ANDROGENI IMPLICATI ACTIUNE REZULTATE NEONATAL T, DHT stimulare Pragatirea tractului genital pentru stimularea ulterioara de la pubertate si la virsta adulta PUBERTATE ORGANE GENITALE INTERNE Stimulare pentru realizarea morfologiei de la adult ORGANE GENITALE EXTERNE FOLICULI PILO-SEBACEI Laringe Schelet Sistem muscular DHT Dezvoltarea pilozitatii androgen dependente si stabilirea ariei caracteristice de distributie Dezvoltarea laringelui cu voce caracteristica Dezvoltarea scheletului dupa model masculin Dezvoltarea musculaturii dupa model masculin

40 EFECTELE ANDROGENILOR – metabolice
TESURI TINTA ANDROGENI IMPLICATI ACTIUNE REZULTATE Metabolism proteic T stimulare Anabolism proteic si deprimarea catabolismului Metabolismul lipoproteinelor Cresterea nivelului LDL, scaderea HDL Hematopoeza Stimularea hematopoezei Controlul secretiei de gonadotropi Comportament sexual T/E DHT Controlul negativ al LH-RH, LH, +/- FSH Stimularea dorintei sexuale si a troficitatii corpilor cavernosi

41 TESTICULUL – determinarea volumului testicular

42 TESTICULUL – ASPECTE ECHOGRAFICE
Determinarea volumului testicular prin calculul arie-lungime-diametru

43 TESTICULUL – ASPECTE ECHOGRAFICE
Hidrocel – zona larga fara echouri care inconjoara testiculul

44 TESTICULUL – ASPECTE ECHOGRAFICE
Testiculul drept are aspect normal Testiculul sting are volum diminuat si hipoechigenitate datorita unei orhidopexii din antecedente Epididimul marit de volum si hipoechogen in cazul unei epididimite acute

45 TESTICULUL – ASPECTE ECHOGRAFICE
Cresterea diametrului plexului pampinifor Cresterea diametrului plexului pampinifor prin manevra Valsalva Reflucul venos in timpul manevrei Valsalva este documentat echoDoppler

46 TESTICULUL – ASPECTE ECHOGRAFICE
Parenchim neomogen cu arii hipo si hiperechogene – seminom pT1 N0 M0 Arii intratesticulare multiple cu aspect chistic, fin limitate cu intarire posterioara de echouri in parenchim testicular cu aspect in rest normal

47 TESTICULUL – ASPECTE ECHOGRAFICE
Zona hipoechogena la polul inferior al testiculului, mici arii hiperechogene in parenchim de altfel normal seminom pT1 N0 M0 Calcificari intratesticulare cu extinctia posterioara de eouri

48 TESTICULUL – ASPECTE ECHOGRAFICE
Mica zona hipoechogena la polul superior al testiculului corespunzind unei tumori cu celule Leydig Mici zone hiperechogene diseminate intr-un parenchim testicular normal –Sindrom “numai celule Sertoli”

49 TESTICULUL

50 EXPLORAREA FUNCTIEI TESTICULARE
TESTOSTERON /FSH/LH TESTOSTERON LH FSH TESTOSTERON LH FSH TESTOSTERON LH FSH HIPOGONADISM HIPOGONADOTROP HIPOGONADISM HIPERGONADOTROP HIPOGONADISM NORMOGONADOTROP

51 HIPOGONADISME HIPOGONADOTROPE CONGENITALE
IZOLATE: Sindromul Kallmann cu anosmie - Xp22.3 mutatie inactivatoare a receptorului de LH-RH ( 4q) mutatie subunitatii  LH – 19q13.32 mutatie a subunitatii  FSH idiopatic ASOCIATE CU ALTE ENDOCRINOPATII: cu hipoplazia congenitala a suprarenalei (DAX1) cu obezitate morbida: mutatia genei leptinei sau receptorului de leptina cu insuficienta hipofizara anteriora : gena Prop-1 ASOCIATE CU ALTE ATINGERI NEUROLOGICE: Sindromul Prader Willi deletia cromozomului 15 patern Sindromul laurence Moon sindromul Bardet Biedl

52 HIPOGONADISME HIPOGONADOTROPE CONGENITALE caracteristici clinice
testicul cu volum sub 5 ml penis sub 5 cm scrot nepigmentat si neted aspect eunucoid vertx-pubis < pubis -sol pilozitate axilara si pubiana redusa sau absenta absenta golfurilor frontale voce infantila mase musculare reduse libido absent retard de maturatie osoasa ostteoporoza

53 SINDROMUL KALLMANN Hypogonadotropic hypogonadism with anosmia or hypoosmia Frequency: 1/10,000 males and 5-7 times less frequent in females - at birth an undescended testis or micropenis evokes the syndrome Familial forms: - X-linked (KAL-1) - autosomal dominant (KAL-2) - autosomal recessif (KAL-3) Other associated abnormalities: neurological: controlateral imitation syncinesis ( mirror movements, visual attention abnormality, abnormalities of ocular movements, ptosis, deafness, non-neurological: aplastic kidney, labial or palatinal dehiscence, dental agenesis

54 SINDROMUL KALLMANN DIAGNOSTIC: T, LH, FSH SCAZUTI, test LH-RH POZITIV
During fetal development Gn-RH secreting neurons have a migration from the medial part of the olfactive epithelium to the hypothalamus in close relationship with olfactory accessory nerves: vomero- nasal and terminal. Than these neurons enter the brain just behind the olfactory bulbs and finally reach the hypothalamus. In a 19 week fetus with x-linked Kallmann’s syndrome the Gn-RH secreting neurons do not reach the hypothalamus and accumulate outside the brain in the nasal region Thus the final way of Gn-RH secreting neurons is dependent of KAL-1 gene. KAL-1 gene encodes a protein named ANOSMINE -1 a nerve-adhesion protein that is not present in nasal epithelium and hypothalamus in Kallmann’s syndrome DIAGNOSTIC: T, LH, FSH SCAZUTI, test LH-RH POZITIV TRATAMENT: LH-RH pulsatil, hCG, hrFSH, testosteron

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64 Obezitatea infantila poate mima un hipogonadism

65 HIPOGONADISME HIPOGONADOTROPE CISTIGATE
Tumori ale regiunii hipotalamo-hipofizare craniofaringiom Adenoame hipofizare disgerminoame, glioame, metastaze hipofizare Procese infiltrative ale regiunii hipotalamo-ipofizare sarcoidoza, histicitoza, hemocromatoza hipofizita sau infundibulita Necroza hipofizara Iatrogenica sau traumatice chirurgie sau / si radioterapia a regiunii hipotalamo-hipofizare traumatism cranian Functionale hiperprolactinemie carente nutritionale hipercortizolism medicamente: androgeni, anabolizante, agonisti de LH-RH, corticoizi

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68 HIPOGONADISME HIPERGONADOTROPE CONGENITALE
Ambiguitate sexuala la nastere: deficit congenital de steroidogeneza: StAR, 17 hidroxilaza, desmolaza, insensibilitate partiala la androgeni deficit de 5  reductaza Criptorhidie vanishing testis sindrom Klinefelter 47, xxy barbati 46 xx, barbati 45,xo mozaicuri SRY+ disgenezie gonadica pura cu cariotip XY

69 HIPOGONADISME HIPERGONADOTROPE CONGENITALE
Adolescenta cu retard pubertar +/- ginecomastie disgenezie gonadica pura XY insensibilitate partiala la androgeni torsiune testiculara leziuni ischemice dupa interventii pt, criptohidie Adult tinar, infertilitate sindrom Klinefelter barbatii 46 xx, SRY+ barbati 47 XYY, alte anomalii ale cromozomului Y anomalii autosomice echilibrate

70 HIPOGONADISME HIPERGONADOTROPE CISTIGATE
orhite: urliana, bacteriana traumatisme testiculare torsiune testiculara, leziuni testiculare arteriale iradiere, chimioterapie medicamente: salazopirina, nitrofuran, colchicina, cloramfenicol, metronidazol toxice profesionale: insecticide, materiale plastice, metale varicocel boli generale debilitante etilism cronic, IRC andropauza – normogonadotropa?

71 Sindromul Klinefelter

72 Sindromul Klinefelter

73 Sindromul Klinefelter
47 XXY, (80 %), 48, XXXY, 49, XXXXY, mozaicuri Frecventa: 1/ 500, sporadic Date clinice: antecedente de criptorhidie atrofie testiculara volum testicular < 4 ml dezvoltare pubertara lenta si incompleta ginecomastie pubertara pilozitate triunghiulara, se rade rar macroschelie osteoporoza deficit intelectual, ataxie (rara) pectus escavatum tulburari de glicoreglare Predispozitie la cancer de sin si tumori cu celule embrionare : choricarcinom, boli autoimune, varice hidrostatice, diabet

74 Sindromul Klinefelter
Date biologice: FSH foarte crescut inhibina B scazuta testosteron total si biodisponibil sub limita inferioara a normalului SHBG crescuta LH superior normalului azoospermie BIOPSIE TESTICULARA Sclero-hialinoza tubilor seminiferi Hiperplazie a celulelor Leydig Insule de spermatogeneza rare in cazuri izolate- ferilizare “in vitro”

75 Sindromul Klinefelter

76 Sindromul Klinefelter

77 TESTICULUL

78 Sindromul Turner masculin

79 Sindromul Turner masculin

80 SINDROM XXXY

81 TESTICULUL

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93 LOSS OF FUNCTION MUTATIONS- clinical phenotype
Gene Receptor Mutation Phenotype Disease Ref. TSH Germline Euthyroidism or hypothyroidism with high TSH levels Resistance to TSH Sunthornthepvarakul T et all. 1995 LH chromosome 2p21 XY male psudohermaphroditism with Leydig cell hypoplasia XX females with partial ovarian failure Male undervirilisation, micropenis Primary or secondary amenorrhea Kremer H et all 1995 FSH Somatic? Primary or early secondary amenorrhea Spermatogenic failure with maintained fertility Oestrogen or /and androgen excess Hypergonadotropic ovarian dysgenesis No disease in males Ovarian sex cord tumours Aitommaki K. et all.1995 Kottlar et all.1997 ACTH Glucocorticoid deficinecy, hyperpigmentation Resistance to ACTH Tsigos C.et all 1993

94 TESTICULUL – Mutatie inactivanta a receptorului LH-R

95 TESTICULUL – Mutatie inactivanta a receptorului LH-R

96 TESTICULUL – Mutatie inactivanta a receptorului LH-R


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