Ormoni sessuali femminili

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Prof. Antonio SINISI
CATTEDRA DI ENDOCRINOLOGIA
SECONDA UNIVERSITA’ DI NAPOLI
ORMONI SESSUALI NELLA DONNA
1. FISIOPATOLOGIA
2. IPOGONADISMO NELLA DONNA
3. IPERPLASIA SURRENALE CONGENITA
4. IRSUTISMO
antonio.sinisi@unina2.it
0815666627
ORMONI SESSUALI NELLA DONNA
OVAIO
SURRENE
E2, A, T, P4
DEA, A, T
E3, E2, A
PLACENTA
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FUNZIONE STEROIDI SESSUALI
NELLA DONNA
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•
•
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DIFFERENZIAZIONE SESSUALE
MATURAZIONE PUBERALE
RIPRODUZIONE
AZIONE SISTEMICA
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PATOLOGIE SFERA RIPRODUTTIVA
NELLA DONNA
• ALTERAZIONI DIFFERENZIAZIONE SESSUALE
• ALTERAZIONI DELLA MATURAZIONE PUBERALE
• ALTERAZIONI
DELLAOVARICA
CICLICITA’ (AMENORREA,
• PATOLOGIA
ANOVULAZIONE,
INFERTILITA’)
• PATOLOGIA SURRENALICA
• IPERANDROGENISMO
• PATOLOGIA MISTA
• TUMORI
• PATOLOGIA IN EPOCA
• ALTERAZIONI SISTEMICHE DA CARENZA/ECCESSO
GRAVIDICA
DI STEROIDI
SESSUALI
OVAIO
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FOLLICULAR PHASE
LUTEAL PHASE
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IPOGONADISMO NELLA DONNA
• EPOCA FETALE: ALTERATA
DIFFERENZIAZIONE SESSUALE
• MANCATO SVILUPPO PUBERALE
• ALTERAZIONI DELLE MESTRUAZIONI
(AMENORREA, OLIGOMENORREA)
• ANOVULAZIONE (INFERTILITA’)
AMENORREA: ASSENZA DI
MESTRUAZIONI
• PRIMARIA: MAI MESTRUAZIONI
• SECONDARIA: ASSENZA DI
MESTRUAZIONI DA > 3 MESI IN
DONNA CHE HA PRESENTATO CICLI
MESTRUALI
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AMENORREA PRIMARIA: assenza del
menarca
CAUSE
4
1. IPOTALAMO-IPOFISARIE
1
2. MALFORMATIVE UTEROVAGINALI
IPOTAL-IPOFISI
3. GONADICHE
3
4. ENDOCRINOPATIE/
OVAIO
PATOLOGIE SISTEMICHE
2
UTERO-VAGINA
AMENORREA PRIMARIA : CAUSE IPOTALAMOIPOFISARIE
LHRH
ipotalamo
LH FSH
ipofisi
estrogeni
ovaio
•
•
•
•
•
•
•
DEFICIT IDIOPATICO DI GONADOTROPINE
SINDROME DI KALLMANN
TUMORI DIENCEFALO-IPOFISARI
TRAUMI, INFEZIONI, GRANULOMI
ANORESSIA NERVOSA
MALATTIE SISTEMICHE GRAVI
RITARDO/ALTERAZIONE COSTITUZIONALE
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IPOGONADISMO IPOGONADOTROPO
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•
•
•
Idiopatico
Sindrome di Kallmann
Funzionale
Panipopituitarismo
AMENORREA PRIMARIA : CAUSE GONADICHE
DI AMENORREA PRIMARIA
LHRH
ipotalamo
LH FSH
ipofisi
estrogeni
ovaio
• DISGENESIA GONADICA:SINDROME DI
TURNER
• FEMMINILIZZAZIONE TESTICOLARE
• DEFICIT 17IDROSSILASI
• AGONADISMO
• PCO
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SINDROME DI TURNER
• DISGENESIA GONADICA O STREAK
GONAD
ST
• BASSA STATURA
• RITARDO PUBERALE/AMENORREA
PRIMARIA
FN
• FSH ALTO, E2 BASSO
• CROMATINA SESSUALE ASSENTE
• CARIOTIPO 45,X O MOSAICISMI X/XX O
ALTERAZIONI STRUTTURALI X (ISOp,
ISOq,rX)
Turner syndrome: state of art
Genetics
• X monosomy is associated with the most
abnormal phenotype, cardiac and renal
•
•
•
•
malformations
Mosaics: mild phenotype, spontaneous menses
up to 40%
Isochromosome: increased risk for autoimmunity
Y material (5-6%): gonadoblastoma
X-Ring: cognitive dysfunction.
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Turner syndrome: state of art
Epidemiology
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•
•
•
3% all female fetuses
7-10% all spontaneous abortions
1 : 2.500 live female births
1.5 million of adult women
• Live expectancy reduced up to 13 yr
• 3-fold increase of overall mortality
(mainly cardiovascular diseases)
Turner syndrome: state of art
Age of diagnosis
Question to clinicians
• Embrio: occasional karyotype analysis
• Fetus: imaging, duo- tri-test
• Birth: c.v. disease, floppy infant, lymphedema (15%)
• Adolescence and Puberty: short stature,
absence of menarche and lack of sexual
characteristics (26%)
• Adulthood: infertility, c.v. sequelae (38%)
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Turner syndrome: state of art
Age of diagnosis
ADOLESCENCE
• SHORT STATURE
• DELAYED PUBERTY
• LACK OF SECONDARY
SEXUAL CHARACTERS
• PARTICULAR FEATURES
ALTERAZIONE
ASPETTI
ALTEZZA
%
100
ENDOCRINE
INTOLL GLUCOSIO,DM2,DM1,
TIROIDITI , IPOTIROIDISMO,
IPERTENSIONE
10-50
15
50
OCCHI
Epicanto
strabismo
20
ORECCHIE
INFEZIONI
SORDITA’
60
30
BOCCA
MICROGNAZIA
PALATO OGIVALE
60
35
COLLO
LINEA POSTERIORE BASSA
CORTO E TOZZO
PTERIGIO
40
40
25
CUTE
AUMENTO DELLE RIGHE
LINFEDEMA
NEVI
IPOPLASIA UNGHIA
30
25
25
10
SCHELETRO
EO RITARDATA
CUBITO VALGO
OSTEOPENIA
IV METACARPO CORTO
GINOCCHIO VALGO
85
50
50-80
35
35
CUORE
V.AORTICA BICUSPIDE
COARTAZIONE AORTA
ANEURISMA
15-30
RENI
A FERRO DI CAVALLO
IPOPLASIA
10
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Turner syndrome: state of art
Short stature
•
Mean final height 143 cm
•
Possible causative roles:
1. Primary bone defect
2. SHOX homeobox gene
3. Partial GH insensitivity
Turner syndrome: state of art
SHOX gene
Expressed on both inactive and active X and Y
chromosome
Isolated mutations of SHOX are associated with short
stature and bone abnormalities sensorineural deafness
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Turner syndrome: state of art
Ovarian Dysfunction
• Most of TS undergo a progressive
degeneration of oocytes, apoptosis of
follicles and ovarian stromal fibrosis, with
gonadal insufficiency
• This is revealed by elevated levels of GnX
(LH, FSH), with low levels of estradiol (E2)
• Most of them have no pubertal development.
Some have regular menses for varying
lengths of time. Rarely they can achieve
pregnancies.
Turner syndrome: state of art
Ovarian Dysfunction
•
Ovarian function is preserved in some
women, with puberty and menses.
1.
2.
Only 8% of X monosomy
47% of mosaics
•
Only few of them maintain that to
fertility (5%), with 40% end with
spontaneous abortion
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Cardiovascular disease
Turner syndrome: state of art
A.
CONGENITAL HEART DISEASE.
Most common in pure 45,X
monosomy, consisting in a series
of abnormalities, first of all
bicuspid aortic valve
B.
AORTIC DISSECTION. Prevalence
estimated to be btw 8-42% ! Risk
factors (GH?):
• Hypertension
• Abnormal aortic valve
• Other left-sided cardiac
malformations
It can be detected by MRI or
Echocardiography
Cardiovascular disease
Turner syndrome: state of art
C. HYPERTENSION. It occurs in children and in adults.
Failure to recognize it may contribute to excess
cardiovascular mortality. No association with
karyotype (influence of therapies). Protection from
estrogens.
D. ISCHEMIC HEART DISEASE. Twice compared with
general population. Risk factors:
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•
•
Insulin resistance, DM2 (up to 50%)
Dyslipidemia
Lack of estrogen protection
Blood pressure, lipids and glucose must be monitored frequently.
MRI or echocardiography must be performed to detect early cv abnormalities
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Endocrine disorders
Turner syndrome: state of art
• THYROID DYSFUNCTION (15yr mean)
– Thyroiditis, up to 40-50 %, mainly in women with
isochromosome
– Hypothyroidism, 25-30 %
• OVARIAN FAILURE
• GLUCOSE METABOLISM
– Most patients have normal fasting glucose and insulin
levels, that rise progressively
• B-cell failure primarily (role of SHOX?)
• Some authors have observed an increase in T1DM
Turner syndrome: state of art
Renal disorders
• Structural abnormalities bw 25-43 %
Early defect
in ureteric
budding
DOUBLE COLLECTING SYSTEM
RENAL AGENESIS
Abnormal
migration of
kidney
PELVIC KIDNEY
HORSESHOE KIDNEY
Potential morbidity (not usually):
1. Pyelonephritis
2. Pelvoureteric obstruction
3. Renovascular hypertension
CHRONIC RENAL
IMPAIRMENT
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Turner syndrome: state of art
Bone Defects
Structural BONE DEFORMATIONS are responsible for
TS stigmata and are mostly related to classic X
monosomy
short legs, shaped chest, wide nipples,
cervical hypoplasia, scoliosis, cubitus valgus,
wide carrying angle, Madelung wrist (bayonet deformity),
genu valgum, short metacarpals, micrognathia,
high arched palate (deletion of connettive-related-gene)
Turner syndrome: state of art
OSTEOPOROSIS affects
a large majority of TS
people
and
responsible
is
for
morbidity
This seems related both to primary bone defect of
mineralization and to estrogen deficiency
Treatment with estrogens and growth hormone improve
to maintain peak bone density, but not to normalize
(fracture risk 3-fold rather than normal people)
No correlations with karyotype
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Turner syndrome: state of art
Hepatitis
High rate of plasma liver enzymes is a common finding in TS
• Transaminase levels upon normal range in 44%
• gamma-GT rises in 47% of subjects
• Infections and alcoholic disease excluded
Histological examination on liver biopsies revealed hepatic fibrosis, vascular
abnormalities, features as newborn liver and fatty infiltrations. The risk of
progression to CIRRHOSIS is unknown, but this condition seems to be 5-fold the
normal population
Controversial role of estrogens
Protective role against hepatic
failure, and reduction in liver
enzymes
transdermal and natural compounds
(E2 valerate)
Rise of serum liver enzymes with
conjugated estrogens.
Deterioration of liver function with
ethinyl-estradiol
Turner syndrome: state of art
Psychosocial Development
• Intellectual function: NORMAL in TS
• Cognitive function:
– impaired nonverbal skills,
– visual-spatial processing,
– motor coordination,
– perceptual abilities (45,X)
• But… … …
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Turner syndrome: state of art
Psychosocial Development
…despite these problems, a significative number
of TS complete a university degree, with
• 33% university (compared to 19% of other
American females)
• 10% postgraduate degree
It remains to solve:
• difficulty to make friends
• problems to enter into sexual relationships
• Poor self-image
Amenorrea primaria
• Femminilizzazione testicolare
• Deficit 17idrossilasi
• agonadismo
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FEMMINILIZZAZIONE
TESTICOLARE
SINDROME
DI MORRIS
PSEUDOERMAFRODITISMO
MASCHILE DA
INSENSIBILITA’
AGLI ANDROGENI
MASCHIO
46,XY
TESTOSTERONE ALTO
FSH LH ALTI
ASSENZA UTERO
VAGINA A FONDO CIECO
TESTICOLI NELL’INGUINE
PSEUDOERMAFRODITISMO
MASCHILE DA
INSENSIBILITA’ PARZIALE
AGLI ANDROGENI
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INSENSIBILITA’ AGLI ANDROGENI
• ALTERAZIONE DEL GENE DEL RECETTORE
DEGLI ANDROGENI
• TESTOSTERONE NON AGISCE
• TUTTI GLI EFFETTI DIFFERENZIATIVI
SULL’APPARATO GENITALE VENGONO
MENO E SI FORMA UN FETO IN SENSO
FEMMINILE (GENITALI ESTERNI)
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DIAGNOSI PEM
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•
•
•
•
•
•
MASCHIO
46,XY
TESTOSTERONE ALTO
FSH LH ALTI
ASSENZA UTERO
VAGINA A FONDO CIECO
TESTICOLI NELL’INGUINE
IPERANDROGENISMO NELLA DONNA
IPERPLASIA SURRENALE CONGENITA
• 21-HYDROXYLASE DEFICIENCY
• 11-HYDROXYLASE DEFICIENCY
• 3BETAHYDROXYSTEROID DEHYDROGENASE D.
TUMORI SURRENALICI
TUMORI OVARICI
PCO
IRSUTISMO IDIOPATICO
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• Ipertricosi è un aumento del vello (peli
non pigmentati, sottili),
• irsutismo è un aumento dei peli
terminali con un pattern di distribuzione
M
• Virilizzazione definisce una condizione
di irsutismo severo associato a
stempiatura ed ipertrofia clitoridea
3
3
2
3
2
2
2
2
2
3
3
3
+
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CAUSE DI IRSUTISMO
1. OVARICHE
2. SURRENALICHE
3. IATROGENE
PCOS
•
•
•
•
•
•
•
IRSUTISMO, AN O IPERANDROGENISMO
INFERTILITA’
ALTERAZIONI MESTRUALI
OBESITA’
LH/FSH
GLUCOSIO/INSULINA <4.5
ESCLUDERE LOAH, IPERTECOSI O TUMORE
AS (Slowey, 2001)
• OVAIA INGRANDITE, MICROPOLICISTICHE
(nel 67-85%)
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