a kuliah reprodmei2014
DESCRIPTION
reproduksiTRANSCRIPT
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REPRODUKSI
LaboratoriumBagian Ilmu Patologi Klinik
Fakultas Kedokteran
UKRIDAMei 2014
Sanarko Lukman Halim
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1. Fungsi Reproduksi
Fungsi reproduksi & kehamilan diatur oleh hormon-
hormon yang sangat kompleks:
Testis: Testosteron
Ovarium: Estradiol, Progesterone
Pituitary: Follicle Stimulating Hormone (FSH)Luteinizing Hormone (LH)
Hypothalamus: Gonadotropin Releasing
Hormone (GnRH)feed back
Placenta: Estrogens & Progesterone
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Pada pria kalau sperma normal tidakperludiperiksa lebih lanjut hormonnya.
semen: cairan+spermatozoa.
Cairan ini pada pria harus alkalis karenaspermatozoa tidak bisa berenang pada suasanaasam.
Reproduksi diatur oleh hormon. Testosteron
pada pria dan wanita bermacam-macam Klinefelter syndrome mungkin bisa punya
anak karena masih ada sel sperma
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Hormon ada feed back ke otak. Contohnya
thyroid hormon. Dia di stimulasi oleh thyroid
stimulating hormone. Kalau tyroxine sudah
cukup maka otak tidak memproduksi TSH lagi.Begitupula sexhormone.
Hipotalamus ada GNRH(gonadotropin releasing
hormone.) pada hiposfise anterior adaFSH(folicle stimulating hormone).
FSH dipakai juga oleh pria walau tidak ada folikel
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Pada wanita menopause maka ovarium tidak
memprouksi estrogen karena mulai atrofi.
Estrogen disingkat E2.
E2 pada menopause>LH>>
Pada yabng mens nya tidak teratur diperiksa
FSH,LH dan E2 untuk tahu hormonnya.
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Plasenta ada juga estrogen dan progesterone.
IgG bisa masuk pada plasenta. Sedangkan IgMtidak dapat melalui plasenta.
Pada bayi baru lahir kemudian ada penyakit,untuk tahu ini penyakit dr ibu atau anak makadiperiksa IgM. Kalau ada IgM brt infeksi pada
bayi. Ini penting untuk pengobatan. Pada bayi bila TSH tinggi maka T4 nya tidak
terproduksi. Begitu juga pada orang dewasa
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The Pituitary-Gonad Axis
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2. Evaluasi Laboratorium
Fungsi Reproduksi:
Pria:Analisa SpermaHasil normal pemeriksaan lanjut tidak perlu.Bila hasil abnormal:perlu evaluasi hormon: Testosteron, FSH, LH.
Indikasi disfungsi reproduksi wanita:
Haid menandakan ada ovulasi.
Amenore dan infertilitasEvaluasi laboratorium:hCG, prolactin, thyroid-stimulating-hormone (TSH),free-thyroxine(fT4), FSH dan LH.
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Pada wanita tuba harus paten agar bisa hamil.
Jadi jika terjadi konsepsi, harus bisa ke uterus.
Jika tidak di uterus berkembangnya maka ini
dinamakan kehamilan ektopik. Ini bisa
berbahaya
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Kasus ujian adalah infertilitas.
SOAL:
Perut membesar apa ini hamil ataukeganasan?
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3. Disfungsi Reproduksi
Indikasi disfungsi reproduksi wanita:amenore, infertilitas
Evaluasi laboratorium:
hCG, prolactin , thyroid stimulating hormone
(TSH), free thyroxine (fT4)
FSH, LH, androgen
Lab tidak diperiksa semuanya. Tergantung
pengalaman dokter
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4. Infertilitas primer Definition: One year of unprotected intercourse
without pregnancy
1: No previous pregnancies
2: Previous pregnancy (not necessarily live birth)
Fecundability: Probability of achieving pregnancywithin a menstrual cycle
20-25% for normally fertile couples
90% of couples should conceive within one year
10-15% of couples experience infertility
Assisted Reproductive TechnologyLaboratorium: Estradiol, Progesterone, hCG
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Pada pasangan infertil pertama periksa
sperma pria. Kalau normal periksa wanita. Tapi
jangan terburu buru karena 15% pasangan
normal belum punya anak pada usiapernikahan 1 tahun
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5. KehamilanIndikasi waktu ovulasi ditentukan dengan tes
urin LH surge ->kemungkinan hamil>>
Awal kehamilan ditentukan dengan tes hCG serum,yang meningkat sekali pada kelanjutan kehamilan.Serum >cepat dari urin. Biasanya pada praktek bayitabung.Untuk praktisnya urin -hCG periksa pd missmenstrual period
hari pertama tidak haid.Konsentrasi hCG yang sangat tinggi (pada
pengenceran urin 1: 200 positif) indikasiadanya mola hidatidosa yg bisa jd coriocarsinomaEclampsia/preeclampsia: (keadaan gawat)
hipertensi,proteinuri
tes protein urin 14
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Dulu untuk menentukan masa subur denganmengukur suhu basal. Jika ada peningkatan inidisebut masa subur.
Sekarang ada LH surge. Kalau meningkat berarti
ada ovulasi HCG bisa dipakai untuk tumor marker juga
hCG ga boleh pada urin suhu lemari es danperiksa pada pagi karena konsentrasi palingtinggi.
Eklamsia dan preeklamsia kalau sudahmelahirkan gejala proteinuria hilang.
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Operasi caesar itu perlu tahu golongan darah,
hb dan faktor resusnya.
Eklamsia: ada gangguan pada ginjal karena
proteinuria.
Pada bayi kuning itu bilirubin indirek dan pada
urin bilirubin negatif
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6. Screening Birth Defect
Trimester pertama-kedua screening
birth defects: chromosomal aneuploidy,
neural tube defects(tulang belakang terbuka karena
kekurangan asam folat). Sindroma Down(kebanyakan
pada wanita usia >35 th. Tp usia muda juga bisa. Infant
stimulating progres-> jika diketahui beresikosyndromdown akan di th/ agar ga jadi syndrome down.)
7. Monitor fetal-hemolyticdisease dengan tes
kadar bilirubin cairan amnion.(bs meninggal karena
ginjal dan hati belom max fungsinya. dan akan timbul
hemoglobinuria)
8. Fetal-lung-maturity: estimasi surfactant paru cairan
amnion: rasio lecithin/sphingomyelin 17
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Pada janin, jika sudah terjadi hemolitik, masihbisa hidup karena ibu bisa mengeliminasibilirubin yang tinggi dari janin. Biasanya di cairan
amnion bilirubin akan meningkat. Pemeriksaanini dinamakan amniosentesis.
Respiratory distress syndrome: kekurangansufaktan pada waktu lahir sehingga susah nafas
sehingga bisa terjadi gagal nafas. Ini terlaluspesialistik tetapi penting diketahui jika diundangkeluar negri bisa saja di tanya.
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9. Toxemia of
Pregnancy(eklamsia)
Hypertensi
Proteinuria tes protein dalam urin
10. Preterm delivery risk
(melahirkan sebelum waktunya)untuk mengetahuinya periksa Fetal
fibronectin cervicalsecretions 19
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Regulasi Reproduksi Pria
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Pada pria yang tidak mau punya anak bisa di
vasectomi sehingga sperma tidak dapat keluar.
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HormonesFollicle-stimulating hormone (FSH) stimulates
spermatogenesis
Interstitial Cell Stimulating Hormone (ICSH) stimulatesthe production of testosterone
testosterone stimulates the development of malesecondary sex characteristics & spermatogenesis.
Testosterone dipakai untuk penilaian laki2 padapraktek.
Terapi testosteron meningkatkan ca prostat
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Pengaturan Reproduksi Wanita
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Ovarium ada 2 kanan dan kiri.
Telur hanya bisa dibuahi oleh 1 sperma.
Haid merupakan masalah yang kompleks karena
nilai hormonnya berlainan sehingga perludiketahui pada hari keberapa setelah haid atausebelum haid. Karena nilai rujukan tergantungpada hari keberapa.
LH tinggi->ovulasi.
Pada mau menopause lebih sulit karena haid gateratur maka nilai saja FSH LH dan E2 nya.
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Haid
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K h il
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Kehamilan
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Endometriosis: nyebabkan kehamilan terganggu.
Kehamilan extrauterine: sangat bahaya karenaperdarahan tidak baik sehingga bisa mati janin
nya. Ini tergantung oleh endometriosis. Darah yang
keluar waktu haid di dalem pelvis. Kalau adajaringan ikat bisa mengganggu patensi tuba.
hCG awalnya ningkat lalu ada fase plateu. Kalauterus meningkat ini mungkin molahidatidosaatau koriokarsinoma.
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Plasenta
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Plasenta
Interlocking fetal and
maternal tissues
Performs digestive,
respiratory, and
urinary functions for
the fetus
Materials exchangedacross membrane
that separates
bloodstreams Figure 44.13Pa e 79129
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Latex Agglutination
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Home Pregnancy Test Kits:PERHATIKAN KONTROL. KALAU KONTROL ga ada
BERARTI HASIL TIDAK DIPERCAYA
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INTERPRETASI
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INTERPRETASI
Negative ResultHCG is not present at detectableconcentrations
Positive ResultPregnancy
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False Positives
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False Positives
Drugs: Antiparkinsonian,anticonvulsants, phenothiazines.
Medical Conditions: Tumors, Recentcompleted pregnancy or miscarriage.Kalau ada abortus hCG jg masih +.
False Negativestoo early, Urine not at room temp.Medical Conditions: Tumors, Recent
completed pregnancy or miscarriage.False NegativesTesting too early,
Urine not at room temp. 33
Hormones and male reproductive function
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Hormones and male reproductive function
FSH (Follicle stimulating hormone)
Targets sustentacular cells to promote
spermatogenesis
LH (leutinizing hormone)
Causes secretion of testosteroneand other
androgens
GnRH (Gonadotropin releasing hormone)
Testosterone
Most important androgen34
D fi i i I f tilit i
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Definisi Infertilitas primer
Infertilitas adalah tidak adanya
kehamilan setelah hubungan suami-isteri selama satu tahun dengan teraturtanpa mengunakan kontrasepsi
Infertility affects 15-20% of couples, or 11million reproductive age people in the U.S.
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F i Ut K l j P i /
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Fungsi Utama Kelenjar Pria/Major Functions of Male Glands
1. 1. Activating spermatozoa
2. 2. Providing nutrients spermatozoa
need for motility
.33. Propelling spermatozoa and fluidsalong reproductive tract:
mainly by peristaltic contractions
.44. Producing buffers:to counteract acidity of urethral and
vaginal environments
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Semen = Sperm + Secretions
Secretions from epididymis aid spermmaturation
Seminal vesicle secretes fructose and
prostaglandins Prostate-gland secretions buffer pH in
the acidic vagina
Bulbourethral gland secretes mucus
Servix ada yang memiliki antibodi terhadap
sperma.37
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Pemeriksaan Dasar Analisa Sperma
The analysis must include:
Volume measurement:kalau vol dikit ga bisabuat hamil.
Concentration determination
Motility assessment: kalau dia ga bisa maju ga
sampai-sampai
Morphology assessment:ada yang kepalabesar
Anti-sperm antibody screen Identification of other cells:ada SDM,trichomonas,
leukosit
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Indikasi Analisa Sperma
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Indikasi Analisa Sperma
1. Assessment of fertility (2-3 samples; 7 days to
3 months - best 2 weeks)2. Forensic purposes (DNA): sekarang bisa
diperiksa DNA dari mukosa mulut jg.
3. Effectiveness of vasectomysamples 1 month apart negative.
Setelah disambung ulang sperma positif
4. Suitability donorfor artificialinsemination(untuk bayi tabung.)
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Persiapan sampel
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Persiapan sampelBy masturbation.
Requires a period of abstinenceprior(3 d)gaboleh ejakulasi selama 3 hari
Must be delivered warmto thelaboratory.sebaiknya di lab dikeluarkannya. Kalaudi negara dingin sperma dimasukin ke dalamjaket agar tidak mati semua.
Can either be produced on site.
Or at home if able to be delivered.2 samples usually needed.
Compared against the
WHO criteria. 40
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Pengambilan Sampel Sperma 1/2
Name Period of abstinence - 2-7days
Time of collection + analysis recorded
Entire ejaculate and not coitus interruptus in a widemouth container
Delivered within 1 hour of collection
Avoid temperature extremes
Ejakulasi retrogard:karena kelainan otot, sperma masukvesika urinaria. Di urin terdapat sperma.
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Pengambilan Sampel Sperma 2/2
If results of 2-3 assessments differ greatly,
additional samples must be analyzed.
If a sperm function test is to be performed, the
sperm must be separated from fluid within 1 hour
of ejaculation.
For vasectomy evaluation, only the presence of
sperm, viable or nonviable is enough.
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Analisa Sperma meliputi pemeriksaan:
Makroskopik
Viscosity:dengan
jarum bisa dilihat
sampai berapa
tinggi ga putus coagulation +
liquifaction
volume
pH
Mikroskopik concentration/count
motility
morphology
viability
Motility &Viability must be
performed
within 1 - 2 hrs of
collection.koleksi ga boleh pake
kondom 43
P ik M k k ik
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Pemeriksaan Makroskopik
Volume: in graduated cylinder to thenearest
0.1 ml or centrifuge tube free of
contamination. Viscosity: 5ml pipette or plastic pipette
normal, more viscous, very viscous
pH: important parameter of motility andviability 7.2-8.0; measured by
pH paper.
Lihat Petunjuk Pemeriksaan Praktikum
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Pemeriksaan Makroskopik
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Pemeriksaan Makroskopik
Semen is viscous, yellow grayish.
Forms gel-like clot immediately.
Liquefies completely in 5-60 minutes; this must
be complete before further testing (mix before
further testing).
Appearance: homogenous white-gray
opalescence.
Brown/red in hematospermia
less opaque if low sperm concentration
Dense white turbid if inflammation and high WBC
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P ik ik k ik
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Pemeriksaan mikroskopik Wet mount:
approximate count
sperm agglutination pattern
viability
motility
morphology
Preparation:
mix
drop on glass slide and apply coverslip
Important: volume (10ul) of semen and thedimensions of the coverslip (22x22) bestandard so that we have fixed depth (20um).
Observe 10-20 using 40x-60x
If number vary from field to field; not mixed46
Sel yang Terlihat
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Sel yang Terlihat
Normally seen: Mature cells make up the greatest percentage of cells
Epithelial cells of genital tract: many in urethritis
Immature germ cells
WBC
Abnormally seen:
Gross bacteria
Trichomonas
Candida
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Motilitas
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Motilitas
While estimating count
No stain
Count 200 total sperm and then the motile
Calculate the percentage
>50% motile
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Aglutinasi
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Aglutinasi
Reported when motile sperm stick to each
other in a definite pattern.Head-head
Tail-tail
Head-tail
Immunological cause of infertility
Done on several HPF
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Spermatozoon Structure
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`
Spermatozoon Structure
Figure 19-4
DNA
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Jumlah Sperma
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Jumlah Sperma
Decreased:
vasectomy (should be 0 after 3-6 months) Varicocele(testis terjadi varises->suhu>>-
>sperma mati)
primary testicular failure (Klinefelters:makadisuntuk testosteron.)
secondary testicular failure
congenital vas obstruction retrograde ejaculation
endocrine causes (prolactinemia, lowtestosterone)
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Common Descriptive Labels
Oligozoospermia(poor count)
Asthenozoospermia
(poor motility)
Teratozoospermia
(abnormal morphology)
Azoospermia
Sperm concentration
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Ringkasan tentang infertilitas
From the above data, it seems that serumprogesterone for detection of ovulation,
hysterography for tubal patency and
semen analysisare the basic essential tests for
diagnosis of infertility.
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Penyebab Infertilitas
Tubal pathology 35%
Male factor 35%
Ovulatory dysfunction 15%
Unexplained 10%
Cervical/other 5%
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Sabar In normal young couples:
25% conceive after one month
70% conceive after six months
90% conceive by one year
Only an additional 5% will conceive in an
additional 6-12 months
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Faktor Pria
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Faktor Pria
Male partner should be evaluated simultaneously
with female
Causes of male infertility:
reversibleconditions (varicocele, obstructive
azoospermia)
not reversible, but viable sperm available (ejaculatory
dysfunction, inoperative obstructive azoospermia)
not reversible, no viablesperm (hypogonadism)
genetic abnormalities testicular or pituitary cancer
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S C
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Sperm Count
Decreased:
vasectomy (should be 0 after 3-6 months)
varicocele
primary testicular failure (Klinefelters)
secondary testicular failure
congenital vas obstruction
retrograde ejaculation
endocrine causes
(prolactinemia, low testosterone)
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Limitations of the procedure :
Delayed examination of the specimen Collection in improper container
Exposure of the specimen to temperature
extremes during transport
Abnormally low sperm count allowing for
evaluation of less than 200 spermatozoa
Use of dirty or contaminated supplies
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Nilai Rujukan/Reference Ranges
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Nilai Rujukan/Reference Ranges
Volume 2.0-6.0 ml
pH 7.2-8.0 **
Count >20 million/ml
Total count > 40 million Morphology > 30% normal form
Viability > 75%(50% in other)
WBC< 1million/ml
RBC none**sperm cannot swim in acidic environments
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Common Descriptive Labels
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p
harus faham
Oligozoospermia
(poor count)
Asthenozoospermia
(poor motility)
Teratozoospermia
(abnormal morphology)
Azoospermia
Sperm concentration
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Evaluasi fungsi Reproduksi Wanita
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Menopos: FSH & LH E2
Tes hormon wanita perhatikan fase
haid
ADAM SyndromeAndrogen Deficiency in the Aging Mananalog dengan Andropause
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Uji Tapis Sindroma Down
Screening sebelum usia kehamilan 20 mg
Trimester pertama antara mg 12-13:diperiksa
-subunit hCG &plasma associated plasma protein (PAPP-A)
fetal chromosomal abnormalities.Ambil darah bisa dari umbilikus sekarang.
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Clinical Features
Central hair whorl (cowlick)
Flat occiput (back of the head)
Upslanting eyes
Epicanthal folds (folds around the corner of the eye)
White spots in the iris of the eye (Brushfield spots)
Upturned nose
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Uji Tapis NTD
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Uji Tapis NTD
Neural Tube Defects
Malformasi kongenital yg sering terlihatUSA 1 per 1000 kehamilan
NTD kegagalan menutupnya neural tube pd hari
ke 27 selelah konsepsi
Di USA pada trimester kedua diperiksa
Serum -fetoprotein (MSAFP)
Diperiksa pada trimester 2
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Example of Closed Unrepaired NTD
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Erythroblastolis Fetalis
Hemolisa darah fetus : aneminormoblastic
hyperplasia normoblastik (erythroblastosis)
kurang oksigen->gagal jantung-hydrops
intrauterine death
Hemoglobinunconjugated bilirubin
cairan amnionspectral analysis 450 nm
Hydrops bisa terjadi pada thalasemia juga.
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BIL>26uG akan merusak otak. Normal pada
hari ketiga ada peningkatan tp kl lebih dari
rujukan dinamakan kern ikteris
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Gestational Diabetes
Intoleransi glukosa pada ibu hamil .
( Lihat kuliah tentang Diabetes)
Diagnosa dan terapi segera utk
mencegahkomplikasi pada ibu dan janinseperti eclampsia, fetal congenital
malformation, fetal makrosomia .
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Fetal Lung Maturity
Fetal Lung maturity produksi surface activephospholipid compound yg disebut surfactant.
Effective gas exchange
Prevent alveolar collapsDefisienRespiratory Distress Sydr(RDS)
Lecithin/sphingomyelin ratio ( L/S test)
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Preeklampsia/Toxemia of Pregnancy
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Preeklampsia/Toxemia of Pregnancy
Preeclampsia adalah sindrome dengan
hipertensi (Sist >140 mm Hg, atau Diast > .90
mm Hg) dgn proteinuria > 0.3 g/l urin 24 jam
pada kehamilan > 20 minggu.
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Infeksi pada Kehamilan
Infeksi viral, bakterial dan parasit berpengaruhpada kesehatan ibu dan janin. (Lihat kuliahmirobiologi, penyakitKulit Kelamin, parasitologi).
HIV, virus hepatitis (A, B,C), virus rubela, virusvarisela, virus sitomegalo, klamidiatrakhomatis, group B streptococcus, Neisseriagonorrhoeae, sifilis, tuberculosis,toksoplasmosis dan malaria .
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Kelainan Hematologi/Koagulasi
Kelainan hematologi dapat berpengaruh
buruk pada ibu dan janin.
Ibu anemi: nutrisional, hemoglobinopati(talasemia), trombositopenia, trombotik
trombositopenia,
Koagulopati ibu (DIC, penyakit von
Willebrand)
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Causes of female infertility
Pelvic factor 50%
Ovulary disorder 30%
Other 15%
Immunology factor 5%
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Thyroid disease and infertility
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Thyroid disease and infertility
Hypothyroidism
Pre-pubertal
Delayed sexual maturation, or rarely,
precocious puberty Post-pubertal
TSH may have leuteotropic effect
Hyperthyroidism
Amenorrhea
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Endometriosis
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Endometriosis
Appearance of endometrial tissue in the
pelvic cavity.
Origin is uncertain
One of the most common diseases of
menstruating women
Involved in 20-50% of infertility cases
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Anti-sperm autoantibodies
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p
1955: Rumke and Hellinga demonstrate association
between humoral autoantibodies to sperm andunexplained infertility
Results were controversial, and hampered by inadequateanalytical techniques
Humoral antibodies do not effect fertility unless theyexist in the reproductive tract
Antibodies must be demonstrated on the spermsurface
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Effect of sperm autoantibodies
Spontantous agglutination
Motility/penetration
Binding to tail
Disruption IgG mediated complement fixation (tail)
Seminal fluid contains complement inhibitors, somembrane attack occurs in the femalereproductive tract
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Anti-sperm antibodies in the female
Clinically significant only in high titers (in serum)
Anti-sperm antibodies may exist in vaginal
secretions or cervical mucus even when humoral
antibodies are not detected
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Diagnosis of immune-related infertility
Post-coital test
Evaluates sperm viability in the cervical mucus
Humoral antibodies
Not diagnostic
Demonstration of antibodies on the sperm
surface
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Desirable characteristics of tumor
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Desirable characteristics of tumor
markers
Easy to measure
Specific for tumor
Always present with tumor
Tapi tidak spesifik dan tidak dianjurkan
pada pasien tanpa gejala
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T f
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Test performance
The sensitivity is 98.0%The specificity is 85%
Liver cancer has anincidence of 1.5:100,000
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U f k
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Use of tumor markers
Screen for disease???
Diagnosis of symptomatic patients
Staging
Prognostic indicators
Detect recurrence of disease
Monitoring response to therapy Radioimmunolocalization
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P t t
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Prostate cancer
2ndmost common cancer (19%), and 2ndleading causeof cancer death, in men
Sensitivity of PSA (at 4.0 g/L) is 78%; specificity isapproximately 33%.
PSA concentration correlates with clinical stage ofcancer
PSA is used to monitor therapy
Meningkat juga pada BPH. Makanya klinis berperan.Kalau cancer meningkat tinggi sekali bisa 500-1000
Prostate-specific antigen
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hCG
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hCG
Awal kehamilan Glycoprotein secreted by the syncytiotropoblastic
cells of the placenta
subunit is shared with LH, FSH, TSH subunit is specific to hCG
Assays can measure intact (sandwich) or bothintact and subunit Cancer patients produce both intact hCG and
subunit
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Use of hCG
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Use of hCG
EarlyPregnancy
Elevated with virtually all trophoblastic tumors C/P Hyatidiformmole
Choriocarcinoma
Elevated in 70% of nonseminomatous testiculartumors
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Alpha-Fetoprotein
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Major fetal protein (70 kd glycoprotein) Synthesized in the yolk sac, fetal liver, GI tract, kidney
Structurally related to albumin
Used as a marker for neural tube defects
Moderate elevations in liver disease(hepatitis/cirrhosis)
Concentrations >1000 g/L are associated withhepatocellular carcinoma
Lower cutoff is used for screening 88
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Carcinoembryonic antigen
Family of up to 36 large, cell-surfaceglycoproteins
Elevated in . . .
70% of colorectal cancers
45% of lung cancers
50% of gastric cancers
40% of breast cancers 55% of pancreatic cancers
25% of ovarian cancers
40% of uterine cancers
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U f CEA
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Use of CEA
Elevated in non-malignant conditions:
Cirrhosis, emphysema, rectal polyps, benignbreast disease, ulcerative colitis
Most useful in staging and
monitoring recurrence ofdisease
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B t
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Breast cancer
Most common malignancy in U.S. women(7% of women develop breast cancer by age
70)
Episialinis expressed by mammaryepithelium
CA 15-3, CA 549, and CA 27.29 arethree distinct epitopes on episialin
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CA 125
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High MW glycoprotein recognized Isolated
from a serous ovarian tumor
Elevated in 50% of stage I ovarian cancer
Elevated in 90%+ of stage II, III, and IV
Overall, sensitivity 95%; specificity 82%; PPV78%; NPV 91%.
Pada Ca ovarium bisa untuk prognosis darikeganasan jika sudah di terapi. Jika timbullagi maka berarti ada kekambuhan.