1
ORMONI SESSUALI NELLA DONNA1. FISIOPATOLOGIA2. IPOGONADISMO NELLA DONNA3. IPERPLASIA SURRENALE CONGENITA4. IRSUTISMO
Prof. Antonio SINISICATTEDRA DI ENDOCRINOLOGIA
SECONDA UNIVERSITA’ DI NAPOLI
ORMONI SESSUALI NELLA DONNA
OVAIO SURRENE
PLACENTA
E2, A, T, P4
E3, E2, A
DEA, A, T
scaricato da www.sunhope.it
2
FUNZIONE STEROIDI SESSUALI NELLA DONNA
• DIFFERENZIAZIONE SESSUALE• MATURAZIONE PUBERALE• RIPRODUZIONE• AZIONE SISTEMICA
scaricato da www.sunhope.it
3
PATOLOGIE SFERA RIPRODUTTIVA NELLA DONNA
• ALTERAZIONI DIFFERENZIAZIONE SESSUALE• ALTERAZIONI DELLA MATURAZIONE PUBERALE• ALTERAZIONI DELLA CICLICITA’ (AMENORREA,
ANOVULAZIONE, INFERTILITA’)• IPERANDROGENISMO• TUMORI• ALTERAZIONI SISTEMICHE DA CARENZA/ECCESSO
DI STEROIDI SESSUALI
• PATOLOGIA OVARICA• PATOLOGIA SURRENALICA• PATOLOGIA MISTA• PATOLOGIA IN EPOCA
GRAVIDICA
OVAIO
scaricato da www.sunhope.it
4
scaricato da www.sunhope.it
5
FOLLICULAR PHASE LUTEAL PHASE
scaricato da www.sunhope.it
6
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
scaricato da www.sunhope.it
7
AMENORREA PRIMARIA: assenza del menarca
CAUSE1. IPOTALAMO-IPOFISARIE2. MALFORMATIVE UTEROVAGINALI3. GONADICHE4. ENDOCRINOPATIE/PATOLOGIE SISTEMICHE
IPOTAL-IPOFISI
OVAIO
UTERO-VAGINA
1
2
3
4
AMENORREA PRIMARIA : CAUSE IPOTALAMO-IPOFISARIE
• DEFICIT IDIOPATICO DI GONADOTROPINE• SINDROME DI KALLMANN• TUMORI DIENCEFALO-IPOFISARI• TRAUMI, INFEZIONI, GRANULOMI• ANORESSIA NERVOSA• MALATTIE SISTEMICHE GRAVI• RITARDO/ALTERAZIONE COSTITUZIONALE
ipotalamo
ipofisi
ovaio
LHRH
LH FSH
estrogeni
scaricato da www.sunhope.it
8
IPOGONADISMO IPOGONADOTROPO
• Idiopatico• Sindrome di Kallmann• Funzionale• Panipopituitarismo
AMENORREA PRIMARIA : CAUSE GONADICHEDI AMENORREA PRIMARIA
• DISGENESIA GONADICA:SINDROME DI TURNER
• FEMMINILIZZAZIONE TESTICOLARE• DEFICIT 17IDROSSILASI• AGONADISMO• PCO
ipotalamo
ipofisi
ovaio
LHRH
LH FSH
estrogeni
scaricato da www.sunhope.it
9
SINDROME DI TURNER
• DISGENESIA GONADICA O STREAK GONAD
• BASSA STATURA• RITARDO PUBERALE/AMENORREA
PRIMARIA• FSH ALTO, E2 BASSO• CROMATINA SESSUALE ASSENTE• CARIOTIPO 45,X O MOSAICISMI X/XX O
ALTERAZIONI STRUTTURALI X (ISOp, ISOq,rX)
FN
ST
GeneticsTurner syndrome: state of art
• X monosomy is associated with the mostabnormal phenotype, cardiac and renalmalformations
• Mosaics: mild phenotype, spontaneous mensesup to 40%
• Isochromosome: increased risk for autoimmunity• Y material (5-6%): gonadoblastoma• X-Ring: cognitive dysfunction.
scaricato da www.sunhope.it
10
Epidemiology• 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
• 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%)
Turner syndrome: state of art
Question to clinicians
scaricato da www.sunhope.it
11
Age of diagnosisADOLESCENCE
• SHORT STATURE
• DELAYED PUBERTY
• LACK OF SECONDARY
SEXUAL CHARACTERS
• PARTICULAR FEATURES
Turner syndrome: state of art
10A FERRO DI CAVALLOIPOPLASIA
RENI
15-30V.AORTICA BICUSPIDECOARTAZIONE AORTAANEURISMA
CUORE
855050-803535
EO RITARDATACUBITO VALGOOSTEOPENIAIV METACARPO CORTOGINOCCHIO VALGO
SCHELETRO
30252510
AUMENTO DELLE RIGHELINFEDEMANEVIIPOPLASIA UNGHIA
CUTE
404025
LINEA POSTERIORE BASSACORTO E TOZZOPTERIGIO
COLLO
6035
MICROGNAZIAPALATO OGIVALE
BOCCA
6030
INFEZIONISORDITA’
ORECCHIE
20Epicantostrabismo
OCCHI
10-501550
INTOLL GLUCOSIO,DM2,DM1, TIROIDITI , IPOTIROIDISMO, IPERTENSIONE
ENDOCRINE
100ALTEZZA
%ASPETTIALTERAZIONE
scaricato da www.sunhope.it
12
Short stature
• Mean final height 143 cm
• Possible causative roles:1. Primary bone defect2. SHOX homeobox gene3. Partial GH insensitivity
Turner syndrome: state of art
SHOX geneExpressed on both inactive and active X and Y
chromosome
Turner syndrome: state of art
Isolated mutations of SHOX are associated with short stature and bone abnormalities sensorineural deafness
scaricato da www.sunhope.it
13
• Most of TS undergo a progressive degeneration of oocytes, apoptosis of follicles and ovarian stromal fibrosis, withgonadal 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 varyinglengths of time. Rarely they can achievepregnancies.
Ovarian DysfunctionTurner syndrome: state of art
• Ovarian function is preserved in some women, with puberty and menses.
1. Only 8% of X monosomy2. 47% of mosaics
• Only few of them maintain that tofertility (5%), with 40% end withspontaneous abortion
Ovarian Dysfunction
Turner syndrome: state of art
scaricato da www.sunhope.it
14
Cardiovascular disease
A. CONGENITAL HEART DISEASE. Most common in pure 45,X monosomy, consisting in a seriesof abnormalities, first of allbicuspid aortic valve
B. AORTIC DISSECTION. Prevalenceestimated to be btw 8-42% ! Riskfactors (GH?):
• Hypertension• Abnormal aortic valve• Other left-sided cardiac
malformationsIt can be detected by MRI or
Echocardiography
Turner syndrome: state of art
Cardiovascular disease
C. HYPERTENSION. It occurs in children and in adults. Failure to recognize it may contribute to excesscardiovascular mortality. No association withkaryotype (influence of therapies). Protection fromestrogens.
D. ISCHEMIC HEART DISEASE. Twice compared withgeneral population. Risk factors:
• 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
Turner syndrome: state of art
scaricato da www.sunhope.it
15
Endocrine disorders• THYROID DYSFUNCTION (15yr mean)
– Thyroiditis, up to 40-50 %, mainly in women withisochromosome
– Hypothyroidism, 25-30 %
Turner syndrome: state of art
• 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
• OVARIAN FAILURE
Renal disorders
• Structural abnormalities bw 25-43 %
Turner syndrome: state of art
Early defectin uretericbudding
DOUBLE COLLECTING SYSTEMRENAL AGENESIS
Abnormalmigration of
kidney
PELVIC KIDNEYHORSESHOE KIDNEY
Potential morbidity (not usually):1. Pyelonephritis2. Pelvoureteric obstruction3. Renovascular hypertension
CHRONIC RENAL IMPAIRMENT
scaricato da www.sunhope.it
16
Bone Defects
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
Structural BONE DEFORMATIONS are responsible forTS stigmata and are mostly related to classic X monosomy
Turner syndrome: state of art
OSTEOPOROSIS affectsa large majority of TS people and isresponsible formorbidity
This seems related both to primary bone defect of mineralization and to estrogen deficiency
Treatment with estrogens and growth hormone improveto maintain peak bone density, but not to normalize(fracture risk 3-fold rather than normal people)
No correlations with karyotype
scaricato da www.sunhope.it
17
Turner syndrome: state of art
HepatitisHigh 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, vascularabnormalities, 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
Protective role against hepaticfailure, and reduction in liver
enzymestransdermal and natural compounds
(E2 valerate)
Rise of serum liver enzymes withconjugated estrogens.
Deterioration of liver function withethinyl-estradiol
Controversial role of estrogens
Psychosocial Development
• Intellectual function: NORMAL in TS • Cognitive function:
– impaired nonverbal skills, – visual-spatial processing, – motor coordination, – perceptual abilities (45,X)
Turner syndrome: state of art
• But… … …
scaricato da www.sunhope.it
18
…despite these problems, a significative numberof TS complete a university degree, with
• 33% university (compared to 19% of otherAmerican females)
• 10% postgraduate degree
Turner syndrome: state of art
Psychosocial Development
It remains to solve:
• difficulty to make friends• problems to enter into sexual relationships• Poor self-image
Amenorrea primaria
• Femminilizzazione testicolare• Deficit 17idrossilasi• agonadismo
scaricato da www.sunhope.it
19
FEMMINILIZZAZIONETESTICOLARE
SINDROMEDI MORRISPSEUDOERMAFRODITISMOMASCHILE DAINSENSIBILITA’AGLI ANDROGENI
MASCHIO46,XYTESTOSTERONE ALTOFSH LH ALTIASSENZA UTEROVAGINA A FONDO CIECOTESTICOLI NELL’INGUINE
PSEUDOERMAFRODITISMOMASCHILE DAINSENSIBILITA’ PARZIALEAGLI ANDROGENI
scaricato da www.sunhope.it
20
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)
scaricato da www.sunhope.it
21
scaricato da www.sunhope.it
22
DIAGNOSI PEM
• 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 SURRENALICITUMORI OVARICIPCOIRSUTISMO IDIOPATICO
scaricato da www.sunhope.it
23
• 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
2
2
2
2
3
3
3
2
2
3
3
+
scaricato da www.sunhope.it
24
CAUSE DI IRSUTISMO
1. OVARICHE2. SURRENALICHE3. 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%)
scaricato da www.sunhope.it
25
scaricato da www.sunhope.it