1.FISIOPATOLOGIA 2.IPOGONADISMO NELLA DONNA … sessuali femminili.pdf · 1.fisiopatologia...

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ORMONI SESSUALI NELLA DONNA1. FISIOPATOLOGIA2. IPOGONADISMO NELLA DONNA3. IPERPLASIA SURRENALE CONGENITA4. IRSUTISMO

[email protected]

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

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FUNZIONE STEROIDI SESSUALI NELLA DONNA

• DIFFERENZIAZIONE SESSUALE• MATURAZIONE PUBERALE• RIPRODUZIONE• AZIONE SISTEMICA


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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


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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

CAUSE1. IPOTALAMO-IPOFISARIE2. MALFORMATIVE UTEROVAGINALI3. GONADICHE4. ENDOCRINOPATIE/PATOLOGIE SISTEMICHE

IPOTAL-IPOFISI

OVAIO

UTERO-VAGINA

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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


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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


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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.


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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%)


Question to clinicians


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Age of diagnosisADOLESCENCE

• SHORT STATURE

• DELAYED PUBERTY

• LACK OF SECONDARY

SEXUAL CHARACTERS

• PARTICULAR FEATURES


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


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Short stature

• Mean final height 143 cm

• Possible causative roles:1. Primary bone defect2. SHOX homeobox gene3. Partial GH insensitivity


SHOX geneExpressed 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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• 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



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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


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



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Endocrine disorders• THYROID DYSFUNCTION (15yr mean)

– Thyroiditis, up to 40-50 %, mainly in women withisochromosome

– Hypothyroidism, 25-30 %


• 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 %


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


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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)


Structural BONE DEFORMATIONS are responsible forTS stigmata and are mostly related to classic X monosomy


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


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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)


• But… … …


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…despite these problems, a significative numberof TS complete a university degree, with

• 33% university (compared to 19% of otherAmerican females)

• 10% postgraduate degree


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


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FEMMINILIZZAZIONETESTICOLARE

SINDROMEDI MORRISPSEUDOERMAFRODITISMOMASCHILE DAINSENSIBILITA’AGLI ANDROGENI

MASCHIO46,XYTESTOSTERONE ALTOFSH LH ALTIASSENZA UTEROVAGINA A FONDO CIECOTESTICOLI NELL’INGUINE

PSEUDOERMAFRODITISMOMASCHILE DAINSENSIBILITA’ PARZIALEAGLI 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

• 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


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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

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+


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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%)


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