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
- Wilmstumour
Frasiers syndrome:
- failure of gonadala differentiation
- gonadoblastoma
WAGR syndrome:
- Wilmstumour
- aniridia
- genital abnormalities, mental retardation
Hiort O., Holterus P-M: The mollecular bases of male sexual diffrentiation. Eur.J.Endocrinol. 2000, v. 142, 101-110

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, 101-110

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
and

SRY mutations were described in true hermaphroditism with both testicular

ovarian tissues development

Hiort O., Holterus P-M: The mollecular bases of male sexual diffrentiation. Eur.J.Endocrinol. 2000, v. 142, 101-110

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, 101110

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, 101-110

DIFERENTIEREA SEXULUI
TESTICUL

DMRT-1, -2

Sertoli

AMH

Leydig - testosteron

SOX 9
SRY

WT-1
LIM-1

MEZODERM
SF-1

GONADA
BIPOTENTIAL
A
DAX 1

OVA
R

ESTROGENI,
PROGESTERON

DIFERENTIEREA SEXULUI

Testiculul
repere
anatomic
e

TESTICULUL ANATOMIE

TESTICULUL HISTOLOGIE

TESTICULUL

SPERMIOGENEZA

CELULA
SERTOLI

TESTICULUL

Defect de P450 aromataza la

barbat
Cromozom 15 q21.1

Faustini-Fustini Marco: Eur.J. Endocrinol, 1999, 140, 111-129

Clinical features in congenital oestrogen deficiency

Female

Male

Fetal life

Mothers transient viriliztion during

seond half of pregnancy

Mothers transient viriliztion during

seond half of pregnancy

External
genitalia at birth

Amiguos genitalia Prader IV-V with a

greatly enlarged phallic-like structureclitoromegaly, 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

Congenital oestrogen deficiency

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

EFECTELE ANDROGENILOR prenatal

ANDROGENI
IMPLICATI

ACTIUNE

CANALELE
WOLF

stimular
e

Dezvoltarea OGI, epididim, canale

deferente

SINUS UROGENITAL

DHT

stimular
e

Dezvoltarea tuberculului genital, a

glandului, fuziunea plicilor uretrale si
genitale cu formarea scrotului,
dezvoltarea prostatei

HIPOTALAMUS
FETAL

T
aromatizat
in
Estradiol

stimular
e

Dezvoltarea sexului neuro-hormonal

masculin cu secretie continua de LH-RH
( lunile IV-VI)

SISTEM
NERVOS
CENTRAL

T, DHT, E2

stimular
e

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

TESURI TINTA

REZULTATE

EFECTELE ANDROGENILOR neonatal, pubertar

ANDROGENI
IMPLICATI

ACTIUNE

NEONATAL

T, DHT

stimulare

Pragatirea tractului genital pentru

stimularea ulterioara de la pubertate si
la virsta adulta

PUBERTATE
ORGANE
GENITALE
INTERNE

T, DHT

stimulare

Stimulare pentru realizarea morfologiei

de la adult

ORGANE
GENITALE
EXTERNE

T, DHT

stimulare

Stimulare pentru realizarea morfologiei

de la adult

FOLICULI PILOSEBACEI
Laringe
Schelet
Sistem
muscular

DHT

stimulare

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

TESURI TINTA

REZULTATE

EFECTELE ANDROGENILOR metabolice

ANDROGENI
IMPLICATI

ACTIUNE

Metabolism
proteic

stimulare

Anabolism proteic si deprimarea

catabolismului

Metabolismul
lipoproteinelor

stimulare

Cresterea nivelului LDL, scaderea HDL

Hematopoeza

stimulare

Stimularea hematopoezei

Controlul
secretiei de
gonadotropi
Comportament
sexual

T/E
DHT

stimulare

Controlul negativ al LH-RH, LH, +/- FSH

Stimularea dorintei sexuale si a
troficitatii corpilor cavernosi

TESURI TINTA

REZULTATE

TESTICULUL determinarea volumului testicular

TESTICULUL ASPECTE ECHOGRAFICE

Determinarea volumului testicular

prin calculul arie-lungime-diametru

TESTICULUL ASPECTE ECHOGRAFICE

Hidrocel zona larga fara echouri care

inconjoara testiculul

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

TESTICULUL ASPECTE ECHOGRAFICE

1.

Cresterea diametrului plexului

pampinifor

2.

Cresterea diametrului plexului

pampinifor prin manevra Valsalva

3.

Reflucul venos in timpul manevrei

Valsalva este documentat
echoDoppler

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

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

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

TESTICULUL

EXPLORAREA FUNCTIEI TESTICULARE

TESTOSTERON /FSH/LH

TESTOSTERON

TESTOSTERON

TESTOSTERON

LH

LH

LH

FSH

FSH

FSH

HIPOGONADISM
HIPERGONADOTROP

HIPOGONADIS
M
NORMOGONAD
OTROP

HIPOGONADISM
HIPOGONADOTROP

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

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

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

SINDROMUL KALLMANN
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 Kallmanns 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
Kallmanns syndrome

DIAGNOSTIC: T, LH, FSH SCAZUTI,

test LH-RH POZITIV

TRATAMENT: LH-RH pulsatil, hCG, hrFSH, testosteron

Obezitatea
infantila
poate mima
un
hipogonadism

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

HIPOGONADISME HIPERGONADOTROPE
CONGENITALE
Ambiguitate sexuala la nastere:
deficit congenital de steroidogeneza: StAR, 17
hidroxilaza, 17-20 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

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

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?

Sindromul Klinefelter

Sindromul
Klinefelter

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

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

Sindromul Klinefelter

Sindromul Klinefelter

TESTICULUL

Sindromu
l Turner
masculin

Sindromul Turner
masculin

SINDROM XXXY

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

TESTICULUL

LOSS OF FUNCTION MUTATIONS- clinical phenotype

Gene
Receptor

Mutation

Phenotype

Disease

Ref.

TSH

Germline

Euthyroidism or hypothyroidism
with high TSH levels

Resistance to TSH

Sunthornthepvar
akul T et all.
1995

LH

Germline
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

Germline
chromosome
2p21
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

Germline

Glucocorticoid deficinecy,
hyperpigmentation

Resistance to ACTH

Tsigos C.et all

1993

ACTH

Kottlar et
all.1997

TESTICULUL Mutatie inactivanta a receptorului LH-R

TESTICULUL Mutatie inactivanta a receptorului LH-R

TESTICULUL Mutatie inactivanta a receptorului LH-R