KORELASI ANTARA ALIRAN DARAH CORPUS LUTEUM
DENGAN KONSENTRASI SERUM PROGESTERON
PADA WANITA INFERTIL
TESIS
OLEH :
BOY RIVAI PANDAPOTAN SIREGAR
DEPARTEMEN OBSTETRI DAN GINEKOLOGI
FAKULTAS KEDOKTERAN UNIVERSITAS SUMATERA UTARA
RUMAH SAKIT UMUM PUSAT H. ADAM MALIK
MEDAN
2011
PENELITIAN INI DIBAWAH BIMBINGAN TIM-5
PEMBIMBING: dr. Binarwan Halim, SpOG (K)
dr. Muhammad Rusda, SpOG (K)
PENYANGGAH : dr. Risman Felix Kaban, SpOG
dr. Indra Gunasti Munthe, SpOG (K)
Prof. dr. M. Fauzie Sahil, SpOG (K)
Diajukan untuk melengkapi tugas-tugas
dan memenuhi salah satu syarat untuk
LEMBAR HALAMAN PENGESAHAN
Penelitian ini telah disetujui oleh Tim 5 ( Lima )
PEMBIMBING :
Dr. Binarwan Halim, SpOG (K) ………
Pembimbing I ....….
MEI 2011Dr. Muhammad Rusda, SpOG (K)
………
Pembimbing
II
.……
MEI 2011PENYANGGAH :
Divisi Feto Maternal
…….
MEI 2011Dr. Indra Gunasti Munthe,SpOG (K)
……….
Divisi Fertilisasi, Endokrinologi
.……
MEI 2011& Reproduksi
Prof. Dr. M. Fauzie Sahil, SpOG (K) ……….
Divisi Onko- Ginekologi
…….
MEI 2011
“ Ya Allah ya Tuhan kami, … bagi-Mu lah segala
puji-pujian, pujian sepenuh langit, pujian sepenuh bumi
dan sepenuh apapun yang Engkau kehendaki
setelah itu …“
( H.R. Muslim )
Kupersembahkan untuk yang Terkasih dan Tercinta Kedua orangtua-ku,
Drs.H.Amir Hood Siregar, Apt, MHA
Dan
(Almh.) Hj. Yunidar Anas
KATA PENGANTAR
Dengan nama Allah Yang Maha Pengasih Lagi Maha Penyayang,
Segala Puji dan Syukur saya panjatkan ke hadirat Allah Subhanahu Wata’ala, Tuhan Yang Maha
Kuasa, berkat Rahmat,Ridho dan Karunia-Nya lah penulisan tesis ini dapat diselesaikan dengan
baik.
Tesis ini disusun untuk melengkapi tugas-tugas dan memenuhi salah satu syarat untuk
memperoleh keahlian dalam bidang Obstetri dan Ginekologi. Sebagai manusia biasa, saya
menyadari bahwa tesis saya ini masih banyak kekurangannya dan masih jauh dari sempurna,
namun demikian besar harapan saya kiranya tulisan sederhana ini dapat bermanfaat dalam
menambah perbendaharaan bacaan khususnya tentang :
“ KORELASI ANTARA ALIRAN DARAH CORPUS LUTEUM DENGAN KONSENTRASI SERUM PROGESTERON PADA WANITA INFERTIL ”
Dengan selesainya laporan penelitian ini, perkenankanlah saya menyampaikan rasa terima kasih
dan penghargaan yang setinggi-tingginya kepada yang terhormat :
1. Rektor Universitas Sumatera Utara Prof.Dr.dr.Syahril Pasaribu, DTM&H, MSc (CTM),
SpA(K) dan Dekan Fakultas Kedokteran Universitas Sumatera Utara, Prof.dr.Gontar
Alamsyah Siregar, SpPD (K-GEH) yang telah memberikan kesempatan kepada saya untuk
mengikuti Program Pendidikan Dokter Spesialis di Fakultas Kedokteran USU Medan.
2. Prof.dr.Delfi Lutan, MSc, SpOG(K), Ketua Departemen Obstetri dan Ginekologi FK-USU
Medan ; dan dr. M. Fidel Ganis Siregar, SpOG, Sekretaris Departemen Obstetri dan
Ginekologi FK-USU Medan
3. dr Henry Salim Siregar, SpOG(K), Ketua Program Studi Pendidikan Dokter Spesialis
Obstetri dan Ginekologi FK-USU Medan ; dr. M. Rhiza Z. Tala, SpOG(K), Sekretaris
Program Studi Pendidikan Dokter Spesialis Obstetri dan Ginekologi FK-USU Medan
4. Prof. dr. R. Haryono Roeshadi, SpOG(K), selaku Kepala Bagian Obstetri dan Ginekologi
Ginekologi FK-USU Medan ; Prof. M. Jusuf Hanafiah, SpOG(K) ; Prof. dr. Hamonangan
Hutapea, SpOG(K) ; Prof. DR. dr. M. Thamrin Tanjung, SpOG(K) ; Prof. dr. Djafar Siddik,
SpOG(K) ; Prof. dr. T.M. Hanafiah, SpOG(K) ; Prof. dr. Budi R. Hadibroto, SpOG(K) ;
Prof. dr. Daulat H. Sibuea, SpOG(K) dan Prof. dr. M. Fauzie Sahil, SpOG(K) yang telah
bersama-sama berkenan menerima saya untuk mengikuti Program Pendidikan Dokter
Spesialis di Departemen Obstetri dan Ginekologi di FK-USU Medan.
5. dr. Binarwan Halim, SpOG(K) yang telah memberikan idenya yang cemerlang kepada saya
untuk melakukan penelitian ini dan sekaligus sebagai Pembimbing Utama Tesis saya
,bersama-sama dengan dr. Muhammad Rusda, SpOG(K) yang juga sebagai pembimbing
tesis saya, yang telah dengan sabar meluangkan waktu dan pikiran yang sangat berharga dan
juga sebagai nara sumber untuk membimbing, mengkoreksi, dan melengkapi penulisan dan
penyusunan tesis ini hingga dapat diselesaikan dengan baik.
6. dr. Risman Felix Kaban, SpOG ; dr.Indra Gunasti Munthe, SpOG(K) ; dan Prof. dr. M.
Fauzie Sahil, SpOG(K), sebagai penyanggah tesis saya, yang juga merupakan nara sumber
yang telah dengan penuh kesabaran meluangkan waktu yang sangat berharga untuk
membimbing, memeriksa, dan melengkapi penulisan tesis ini hingga dapat diselesaikan
dengan baik.
7. Dr Ichwanul Adenin, SpOG(K), selaku Ketua Divisi Fertilisasi dan Endokrinologi
Reproduksi atas kesempatan yang diberikan kepada saya untuk dapat melakukan penelitian
di Bidang Fertilisasi dan Endokrinologi Reproduksi di Departemen Obstetri dan Ginekologi
FK-USU .
8. Ucapan Terimakasih yang tak terhingga kepada dr. Binarwan Halim, SpOG(K) beserta
seluruh Staff ,Paramedis dan Karyawan / ti “Halim Fertility Center” Medan yang telah
mengizinkan saya dan banyak sekali memberikan bantuan kepada saya, selama saya
melakukan penelitian di “Halim Fertility Center” Medan. Semoga Tuhan membalas
9. Kepada dr. Surya Dharma, MPH, Drs.Abdul Jalil Amri,M.Kes dan dr.Arlinda Sari
Wahyuni,M.Kes, sebagai pembimbing statistik Tesis saya ,yang telah dengan penuh
kesabaran meluangkan waktu dan pikiran untuk membimbing dan membantu saya dalam
penyelesaian uji statistik tesis ini.
10. dr.Yusuf R Surbakti, SpOG(K), selaku pembimbing Referat Fetomaternal saya yang
berjudul ”Penatalaksanaan Thrombo Emboli Vena dalam Kehamilan” ; Kepada dr.
Syamsul Arifin Nasution, SpOG(K) selaku pembimbing Referat Fertilitasi, Endokrinologi
dan Reproduksi saya yang berjudul ”Penggunaan Selective Progesterone Receptor
Modulator pada Pengobatan Endometriosis dan Myoma Uteri” dan kepada dr. John S. Khoman, SpOG(K) selaku pembimbing Referat Onko-Ginekologi saya yang berjudul
”Pseudomyxoma Peritonei”. Terimakasih atas bimbingan dan arahan yang diberikan kepada saya , selama saya menyelesaikan referat referat saya tersebut.
11. dr. Einil Rizar, SpOG(K), selaku Bapak Angkat saya ,selama saya menjalani masa
pendidikan di Departemen Obstetri dan Ginekologi FK-USU, yang telah banyak
mengayomi, membimbing dan memberikan nasehat-nasehat yang bermanfaat kepada saya
dalam menghadapi masa-masa sulit selama masa pendidikan.
12. Seluruh Staf Pengajar di Departemen Obstetri dan Ginekologi FK-USU Medan / RSUP
H.Adam Malik / RSUD Dr.Pirngadi Medan, yang secara langsung telah banyak
membimbing dan mendidik saya sejak awal hingga akhir pendidikan.
13. Kepada Sekretariat Bersama Fakultas Kedokteran se-Indonesia (CHS) dan Kepala Dinas
Kesehatan Propinsi Sumatera Utara, atas izin yang telah diberikan kepada saya untuk
mengikuti Program Pendidikan Dokter Spesialis Obstetri dan Ginekologi di Fakultas
14. Direktur RSUP. H. Adam Malik Medan ; dan Ketua SMF Kebidanan dan Penyakit
Kandungan RSUP H.Adam Malik , beserta seluruh staf ,para Bidan dan seluruh paramedis
yang telah memberikan kesempatan dan sarana serta bantuan kepada saya untuk bekerja
selama mengikuti pendidikan dan selama saya bertugas di SMF Kebidanan dan Penyakit
Kandungan RSUP H.Adam Malik Medan.
15. Direktur RSUD Dr. Pirngadi Medan ; dan Ketua SMF Kebidanan dan Penyakit Kandungan
RSUD Dr.Pirngadi Medan dr. Rushakim Lubis, SpOG beserta seluruh staff-nya ,para Bidan
dan seluruh paramedis yang telah memberikan kesempatan dan sarana serta bantuan kepada
saya untuk bekerja selama mengikuti pendidikan dan selama saya bertugas di SMF
Kebidanan dan Penyakit Kandungan di RSUD Dr.Pirngadi Medan.
16. Direktur RS. PTPN 2 Tembakau Deli Medan ;dan Kepala SMF Kebidanan dan Penyakit
Kandungan RS PTPN 2 Tembakau Deli Medan dr. Sofian Abdul Ilah, SpOG dan juga dr.
Nazaruddin Jaffar, SpOG(K) ; beserta staf ,para Bidan dan Paramedis yang telah
memberikan kesempatan dan sarana kepada saya dan membantu saya selama bertugas di
Rumah Sakit tersebut.
17. Direktur RS Haji Mina Medan ;dan Kepala SMF Kebidanan dan Penyakit Kandungan RS
Haji Mina Medan ,dr Muslich Peranginangin, SpOG beserta seluruh staff ,para Bidan dan
seluruh paramedis yang telah memberikan kesempatan dan sarana serta membantu saya
untuk bekerja selama bertugas di Rumah Sakit tersebut.
18. Direktur RS Sundari Medan dan Kepala SMF Kebidanan dan Penyakit Kandungan RS
Sundari Medan dr Muhammad. Haidir, SpOG beserta staff, dan Ibu Hj.Sundari,Amkeb
beserta para Bidan dan seluruh paramedis yang telah memberikan kesempatan dan sarana
kepada saya untuk bekerja selama bertugas di Rumah Sakit tersebut.
19. Ka. RUMKIT Tk. II KesDam II / Bukit Barisan ” Puteri Hijau” ; dan Kepala SMF
Kebidanan dan Penyakit Kandungan di RUMKIT Tk.II KesDam II / Bukit Barisan Mayor
di RUMKIT Tk.II KesDam II / Bukit Barisan ”Puteri Hijau” yang telah memberikan
kesempatan dan sarana serta bantuan kepada saya untuk bekerja selama bertugas di Rumah
Sakit tersebut.
20. Distrik Manager PTPN 3 Distrik Pamela dan Manager RS PTPN 3 Sri Pamela, Tebing
Tinggi, dan Kepala SMF Kebidanan dan Penyakit Kandungan RS PTPN 3 Sri Pamela,
Tebing Tinggi, beserta seluruh staf,para Bidan dan seluruh paramedis yang telah
memberikan kesempatan kerja ,memberikan bantuan sarana dan bantuan moril selama saya
bertugas di rumah sakit tersebut.
21. Dinas Kesehatan Kota Tebing Tinggi ,IDI dan POGI Kota Tebing Tinggi atas bantuan dan
perlindungan kepada saya selama saya bertugas di Tebing Tinggi. Khusus kepada dr.Budi
Santoso, SpOG ,dr.Rosnaliza Harahap, SpOG dan dr.Maria Novita Adelina Pardede, SpOG
,saya menghaturkan banyak terimakasih atas bantuan dan bimbingan selama saya bertugas
di Tebing Tinggi. Semoga Tuhan membalas kebaikan anda.
22. Ketua Departemen Anestesiologi dan Reanimasi FK USU / RSUP H.Adam Malik Medan
beserta seluruh staff, atas kesempatan dan bimbingan yang telah diberikan selama saya
bertugas di Departemen tersebut.
23. Ketua Departemen Patologi Anatomi FK-USU beserta seluruh staf, atas kesempatan dan
bimbingan yang telah diberikan selama saya bertugas di Departemen tersebut.
24. Kepada senior-senior saya, Terimakasih banyak atas segala bimbingan, bantuan dan
dukungannya yang telah diberikan kepada saya selama ini. Semoga Allah SWT membalas
budi baik yang saya terima dari mereka selama ini.
25. Teman-teman seangkatan saya: dr. Muhammad Jusuf Rachmatsyah, SpOG; dr. Teuku
Jeffrey Abdillah, SpOG; dr.Sri Jauharah Laily, SpOG; dr. Made Surya Kumara, SpOG; dr.
Muhammmad Rizki Yaznil, SpOG; dan dr. Yuri Andriansyah, Terima kasih untuk
26. Kepada yunior-yunior saya, saya menyampaikan sedalam-dalam terima kasih dan rasa
syukur alhamdulillah atas segala dukungan dan bantuan yang diberikan selama ini serta
kebersamaan kita selama pendidikan. Semoga kebersamaan dan kerjasama kita tetap
terpelihara dan Allah SWT melindungi kita semua.
27. Kepada yang tersayang ,tim Jaga ku. Tiada saat yang paling indah selain di waktu jaga kita
bersama selama ini. Rasa Syukur dan Terimakasih yang sebesar-besarnya atas bantuan dan
kerjasama yang kompak diantara kita selama ini. Semoga kebersamaan dan kekompakan
kita tetap terpelihara, dan kita semua senantiasa dalam lindungan Allah SWT.
28. Seluruh teman sejawat PPDS yang tidak dapat saya sebutkan satu persatu, terima kasih atas
kebersamaan, dorongan semangat dan doa yang telah diberikan .
29. Seluruh Teman Sejawat Dokter Muda, para Bidan, seluruh Paramedis, serta para pasien di
Departemen Obstetri dan Ginekologi FK USU / RSUP. H. Adam Malik – RSU. Dr. Pirngadi
Medan dan RS Jejaring yang daripadanya saya banyak memperoleh pengetahuan baru,
terima kasih atas kerja sama dan saling pengertian yang baik, yang diberikan kepada saya
selama ini ,sehingga saya dapat sampai pada akhir program pendidikan ini.
30. Para karyawan / karyawati yang banyak membantu saya selama menjalani masa pendidikan
di Departemen Obstetri dan Ginekologi FK-USU, Ibu Asnawati Hasibuan, Ibu Sosmalawati
Harahap, Ibu Nur Asmawati, Ibu Zubaedah, Ibu Jas, Ibu Nurmawan, Mimi Rahmi ,Rifda
Astuti, Winta, Yus Sari Asih. Terimakasih atas bantuan dan kerjasamanya selama saya
menjalani pendidikan di Departemen Obstetri dan Ginekologi FK-USU / RSUP H.Adam
Malik / RSU Dr. Pirngadi Medan.
Sembah sujud, setinggi-tinggi hormat dan sedalam-dalam terima kasih yang tidak terhingga dari
lubuk hati sanubari yang paling dalam ,saya sampaikan kepada kedua Orang Tua saya yang saya
cintai dan saya sayangi, Ayahanda Drs.H.Amir Hood Siregar, Apt, MHA dan Ibunda (Almh.)
orangtua yang telah membesarkan, membimbing, mendoakan, serta mendidik saya dengan penuh
kasih sayang dari sejak saya kecil hingga saat ini, memberi contoh yang baik dalam menjalani
hidup ,serta memberikan motivasi dan semangat serta dukungan kepada saya selama saya
mengikuti pendidikan ini. Semoga Allah SWT melindungi kita semua.
Kepada abangku tersayang Rachmad Saleh Siregar, ST ; dan kakak iparku Rika Yulisa
Rachmad Saleh, S.IP, M.HRD Science ( Hons.) dan adikku tersayang Fifi Savitri Siregar, B.Comp Science ( Hons,), M.M .Dan juga kepada ibunda Siti Rodiah, S.E .Terima kasih atas dorongan semangat serta doa yang diberikan kepada saya ,sehingga saya dapat menyelesaikan
program pendidikan ini. Tanpa pengorbanan, doa, dorongan ,semangat dan dukungan dari kalian
semua, tidak mungkin tugas tugas ini semua dapat saya selesaikan.
Kepada yang terhormat, Om dr.H.Sjahrial Refli Anas, MHA dan Tante Hj. Getrina Fezienty
Sjahrial. Terimakasih yang sebesar-besarnya atas dukungan, bantuan, doa dan semangat yang diberikan kepada saya selama ini.Tiada kata terindah selain ungkapan rasa syukur dan
terimakasih yang teramat dalam atas bantuan Om dan Tante selama saya menjalani masa
pendidikan ini. Semoga Allah SWT membalas kebaikan Om dan Tante.
Akhirnya kepada seluruh keluarga besar saya, Keluarga besar Alm.Bokar Siregar glr Sutan
Pandapotan Muda dan Keluarga besar Anas Sofyan glr Datuak Rajo Sutan, serta seluruh handai
taulan semua yang tidak dapat saya sebutkan namanya satu persatu, baik secara langsung
maupun tidak langsung, yang telah banyak memberikan bantuan,doa dan dukungan, baik moril
maupun materiil, saya ucapkan banyak terima kasih.
Semoga Allah Subhanahu wa Ta’ala senantiasa melimpahkan rahmah dan barokah-Nya kepada
kita sekalian. Amin
Medan, Mei 2011
KORELASI ANTARA ALIRAN DARAH CORPUS LUTEUM DENGAN KONSENTRASI SERUM PROGESTERON PADA WANITA INFERTIL
Siregar B R P, Halim B, Rusda M
Departemen / SMF Obstetri dan Ginekologi
Fakultas Kedokteran Universitas Sumatera Utara / RSUP H. Adam Malik / Unit/Sub-Divisi Teknologi Reproduksi Bayi Tabung, Divisi FER,Dept Obgyn FK-USU
”Halim Fertility Centre” Medan
--- ABSTRAK
Tujuan : Tujuan penelitian ini adalah untuk mengetahui Adakah Korelasi yang signifikan antara Aliran darah Corpus Luteum dengan Konsentrasi serum Progesteron pada Fase Luteal wanita infertil.Dan untuk menilai parameter manakah dari Aliran Darah Corpus Luteum yang menjadi Prediktor terbaik untuk menegakkan diagnosa Defek Fase Luteal sebagai parameter diagnostik alternatif selain melalui penilaian Kadar Serum Progesteron
Rancangan Penelitian :Penelitian ini merupakan suatu penelitian survei analitik dengan menggunakan rancangan potong lintang (cross sectional study),dilaksanakan di Unit / Sub-Divisi Teknologi Reproduksi Bayi Tabung, Divisi FER, Dept Obgin ,FK-USU “HalimFertility Centre”, Medan,berlangsung dimulai dari 1 November 2010 sampai dengan 30 April 2011. Sampel penelitian adalah semua wanita infertil yang merupakan wanita usia reproduksi ( 15 – 45 tahun ) yang yang dilakukan dengan Consecutive Sampling diseleksi menurut kriteria inklusi dan eksklusi yang datang memeriksakan diri ,kemudian yang memenuhi kriteria inklusi dan bersedia ikut serta,diambil sebagai sampel penelitian.Dengan rumus Korelasi Pearson (r = 0.433) dari liteartur, didapatkan sebanyak 41 sampel. Data – data yang dikumpulkan dibuat dalam Tabulasi Induk, diolah secara komputerisasi dengan menggunakan SPSS versi 19.0. Data disajikan dengan nilai Rata-rata ± Standar Deviasi . Data disajikan dalam bentuk Grafik Scattered Dot. Untuk melihat hubungan signifikansi antar variabel dilakukan dengan analisis korelasi Pearson dan dinyatakan bermakna jika nilai p < 0.05, dan dengan menggunakan nilai r untuk melihat kuatnya hubungan antar variabel penelitian. Hubungan akan semakin kuat jika mendekati nilai +1 atau -1Arah korelasi dinyatakan positif (+) jika ditemukan variabel yang satu berbanding lurus dengan variabel yang lainnya dan negatif (-) jika ditemukan variabel yang satu berbanding terbalik dengan variabel yang lainnya
Material dan Metode Penelitian : Tiap responden yang memenuhi kriteria inklusi masing masing diberikan Chart Suhu Basal Badan untuk dicatat suhu basal badannya pada pagi hari setiap hari selama 28 hari. Hari ke 14 diperkirakan merupakan suhu terendah selama siklus, dan dinyatakan sebagai hari ovulasi. Setelah ovulasi, terbentuk Corpus Luteum yang memproduksi Progesteron. Puncak fase Luteal yaitu 7 hari setelah ovulasi. Pada hari ke 21 pasien diminta datang untuk dilakukan pemeriksaan konsentrasi serum progesteron,dan selanjutnya dilakukan USG Power Doppler Transvaginal untuk menilai Aliran darah Corpus Luteum (PSV,EDV,PI,RI,Volume Corpus Luteum), kemudian data dikumpulkan sampai 41 sampel terpenuhi dan ditabulasi, lalu dilakukan Uji Korelasi Pearson.
dengan nilai r = 0.002. Diperoleh nilai cut off point dari Pulsatility Index (PI) sebagai alat diagnostik yang paling baik nilai AUC-nya (AUC=70,1%) dibandingkan dengan variabel-variabel prediktor (alat diagnostik ) lainnya pada defek fase luteal adalah 1,085 dengan sensitivitas 73,3 % dan spesifisitas 66,7 %.
Kesimpulan : Ada korelasi yang bermakna antara Peak Systolic Velocity (PSV) Aliran Darah Corpus Luteum dengan Konsentrasi Serum Progesteron dan ditemukan hubungan korelasi positif dengan Kekuatan Korelasi sedang. Ada korelasi yang bermakna antara End Diastolic Velocity (EDV) Aliran Darah Corpus Luteumdengan Konsentrasi Serum Progesteron dan ditemukan hubungan korelasi positif dengan Kekuatan Korelasi kuat. Ada korelasi yang bermakna antara Pulsatility Index Aliran Darah Corpus Luteum dengan Konsentrasi Serum Progesteron dan ditemukan hubungan korelasi negatif dengan Kekuatan Korelasi lemah .Ada korelasi yang bermakna antara
Resistance Index Aliran Darah Corpus Luteum dengan Konsentrasi Serum Progesteron dan ditemukan hubungan Korelasi negatif dengan Kekuatan Korelasi sedang. Ada Korelasi yang tidak bermakna antara Volume Corpus Luteum (mm3)dengan Konsentrasi Serum Progesteron dan ditemukan hubungan korelasi positif dengan kekuatan Korelasi sangat lemah Diperoleh nilai Pulsatility Index (PI) sebagai nilai untuk alat diagnostik yang paling baik , dimana nilai AUC-nya (AUC=70,1%) dibandingkan dengan variabel-variabel prediktor (alat diagnostik ) lainnya pada defek fase luteal ,dengan nilai cut-off point nya adalah 1,085 dengan sensitivitas 73,3 % dan spesifisitas 66,7 %.
Kata Kunci : Suhu Basal Badan, Volume Corpus Luteum, Peak Systolic Velocity, End Diastolic Velocity, Pulsatility Index, Resistance Index, Konsentrasi serum Progesteron,Defek Fase Luteal.
DAFTAR ISI
PEMBIMBING PENELITIAN………. i
LEMBAR PENGESAHAN PENELITIAN………..ii
KATA PENGANTAR………...iv
ABSTRAK TESIS………xiii
DAFTAR ISI……….…xv
DAFTAR GAMBAR………....xix
DAFTAR TABEL……….xx
DAFTAR GRAFIK………..xxi
DAFTAR SKEMA………. .xxii
DAFTAR SINGKATAN………...xxiii
DAFTAR LAMPIRAN………...….xxv
BAB I PENDAHULUAN I.1 LATAR BELAKANG...1
I.2 RUMUSAN MASALAH………. ...7
I.3 TUJUAN PENELITIAN ...7
I.3.1 TUJUAN UMUM………..7
I.3.2 TUJUAN KHUSUS ...7
I.4 HIPOTESIS PENELITIAN...8
I.5 MANFAAT PENELITIAN ...8
II.2 TUMBUH KEMBANG CORPUS LUTEUM ...9
II.3 PATHWAY STEROIDOGENIK LUTEAL ...10
II.4 REGULASI FUNGSI LUTEAL ...12
II.5 ANGIOGENESIS CORPUS LUTEUM ...13
II.5.1 PENDAHULUAN ...13
II.5.2 FAKTOR-FAKTOR YANG MEMPENGARUHI ANGIOGENESIS CORPUS LUTEUM...14
II.5.2.1 PERUBAHAN DALAM JUMLAH PERISIT ...14
II.5.2.2 STABILISASI PEMBULUH DARAH ...15
II.5.3 FAKTOR ANGIOGENIK...15
II.5.3.1 FAKTOR PERTUMBUHAN ENDOTELIAL ...15
II.5.3.2 ANGIOPOEITIN...15
II.5.4 REGULASI MOLEKULER ANGIOGENESIS CORPUS LUTEUM ...17
II.5.5 ANGIOGENESIS DAN FUNGSI LUTEAL ...18
II.6 DETEKSI ALIRAN DARAH LUTEAL PADA CORPUS LUTEUM ...19
II.7 PENILAIAN ANGIOGENESIS CORPUS LUTEUM ...19
II.7.1 VOLUME CORPUS LUTEUM...20
II.7.2 PEAK SYSTOLIC VELOCITY (PSV) DAN EDV (END DIASTOLIC VELOCITY) ALIRAN DARAH CORPUS LUTEUM ...20
II.7.3 INDEKS PULSATILITAS (PI=PULSATILITY INDEX) ...20
II.7.4 INDEKS RESISTENSI (RI= RESISTANCE INDEX) ...21
II.8 KONSENTRASI SERUM PROGESTERON...22
II.8.1 PERAN PROGESTERON PADA SUMBU HIPOTHALAMUS-HIPOFISIS...22
II.8.3 DEFEK FASE LUTEAL ...25
II.9 PENENTUAN DEFISIENSI SEKRESI PROGESTERON OLEH CORPUS LUTEUM
PADA FASE LUTEAL ...25
II.9.1 SAAT OVULASI DAN PEMBENTUKAN CORPUS LUTEUM ...25
II.9.2 PENGUKURAN SUHU BASAL BADAN
(BBT=BASAL BODY TEMPERATURE)...26
II.9.3 PENENTUAN PANJANG FASE LUTEAL ...28
II.9.4 PEMERIKSAAN KONSENTRASI SERUM PROGESTERON FASE LUTEAL...28
II.9.5 PEMANTAUAN DENGAN ULTRASONOGRAFI...29
II.9.6 BIOPSI ENDOMETRIUM ...29
II.10 HUBUNGAN ALIRAN DARAH CORPUS LUTEUM DENGAN
KONSENTRASI SERUM PROGESTERON ...30
II.10.1 HUBUNGAN PEAK SYSTOLIC VELOCITY (PSV) DENGAN
KONSENTRASI SERUM PROGESTERON PADA FASE MID-LUTEAL ...31
II.10.2 HUBUNGAN END DIASTOLIC VELOCITY (EDV) DENGAN
KONSENTRASI SERUM PROGESTERON PADA FASE MID-LUTEAL ...32
II.10.3 HUBUNGAN PULSATILITY INDEX (PI) DENGAN KONSENTRASI
SERUM PROGESTERON PADA FASE MID-LUTEAL ...33
II.10.4 HUBUNGAN RESISTANCE INDEX (RI) DENGAN KONSENTRASI
SERUM PROGESTERON...34
II.10.5 HUBUNGAN VOLUME CORPUS LUTEUM DENGAN KONSENTRASI
SERUM PROGESTERON...36
BAB III METODE PENELITIAN
III.2 TEMPAT DAN WAKTU PENELITIAN...39
III.3 POPULASI DAN SAMPEL PENELITIAN III.3.1 POPULASI PENELITIAN ...39
III.3.2 SAMPEL PENELITIAN...39
III.3.3 BESAR SAMPEL PENELITIAN...40
III.3.4 KRITERIA SAMPEL III.3.4.1 KRITERIA INKLUSI ...41
III.3.4.2 KRITERIA EKSKLUSI...41
III.4 MATERIAL DAN METODE PENELITIAN III.4.1 MATERIAL ALAT PENELITIAN ...41
III.4.2 MATERIAL BAHAN PENELITIAN...42
III.4.3 METODE/ CARA KERJA PENELITIAN ...42
III.5 ALUR PENELITIAN ...51
III.6 VARIABEL PENEITIAN ...52
III.7 KERANGKA KONSEP PENELITIAN ...52
III.8 BATASAN OPERASIONAL PENELITIAN...54
III.9 PENGOLAHAN DATA ...56
III.10 ETIKA PENELITIAN ...57
BAB IV HASIL PENELITIAN DAN PEMBAHASAN...59
BAB V KESIMPULAN DAN SARAN V.1 KESIMPULAN...89
DAFTAR GAMBAR
Gambar 1 Penyebab infertilitas pada pasangan suami-istri ... 1
Gambar 2 Fase Proliferasi Endometrium / Fase Folikuler Ovarium ,Ovulasi dan Fase Sekresi Endometrium / Fase Luteal Ovarium Siklus Menstruasi Wanita ... 3
Gambar 3 Sel Theca Lutein dan Sel Granulosa Lutein... 10
Gambar 4 Tumbuh Kembang Corpus Luteum... 10
Gambar 5 Pathway Biosintesis Progesteron dalam Sel-sel Luteal ... 11
Gambar 6 Siklus Hidup Corpus Luteum... 12
Gambar 7 Hipotesis Regulasi perubahan pembuluh darah oleh VEGF, Angiopoietin-1, dan Angiopoietin-2 selama perkembangan dan regresi Corpus Luteum ...16
Gambar 8 Mekanisme biomolekuler Angiogenesis dalam Corpus Luteum selama siklus Menstruasi dan pada Awal Kehamilan ...18
Gambar 9 Hasil Scaning Aliran Darah (Angiogenesis) Corpus Luteum dalam Ovarium ... 21
Gambar 10Interpretasi Hasil Scanning Aliran Darah ( Angiogenesis ) Corpus Luteum Dalam Ovarium Pada USG Doppler Transvaginal... 22
Gambar 11Gambaran Mekanisme Hipothalamus Hipofisis Ovarium dalam Mempengaruhi Corpus Luteum Memproduksi Progesteron ... 23
Gambar 12Representasi Skematik perubahan vaskularisasi selama hidup Folikel tunggal yang diseleksi untuk menjadi matang dan ber-Ovulasi ... 25
Gambar 13Rekaman Suhu Basal Badan Ideal ... 26
Gambar 14Contoh TABEL BBT ( BASAL BODY TEMPERATURE ) IDEAL ... 44
Gambar 15Ilustrasi Penggunaan Usg Doppler Transvaginal ………..47
Doppler Transvaginal………49
Gambar 17Hasil Scanning Aliran Darah ( Angiogenesis ) Corpus Luteum Dalam
DAFTAR TABEL
Tabel 2.1 Peran Progesteron untuk Implantasi dan Perkembangan Folikel ... 23
Tabel 4.1 Hubungan peak systolic velocity (PSV) aliran darah corpus luteum dengan konsentrasi serum progesteron...59
Tabel 4.2 Hubungan end diastolic velocity (EDV) aliran darah corpus luteum dengan konsentrasi serum progesteron...62
Tabel 4.3Hubungan pulsatility index (PI) alirandarah corpus luteum dengan konsentrasi serum progesteron...63
Tabel 4.4Hubungan resistance index (RI) aliran darah corpus luteum dengan konsentrasi serum progesteron...67
Tabel 4.5 Hubungan volume corpus luteum dengan konsentrasi serum progesteron...69
Tabel 4.6.1 Sebaran subyek penelitian berdasarkan karakteristik umur………72
Tabel 4.6.2 Sebaran subyek penelitian berdasarkan karakteristik BMI………72
Tabel 4.6.3 Sebaran subyek penelitian berdasarkan karakteristik kadar serumProgesteron…….73
Tabel 4.7 Distribusi perbedaan rata – rata dari variabel-variabel prediktor terjadinya defek fase luteal yang dikategorikan berdasarkan kadar serum progesterone < 10 ng/ml dan >10ng/dl……74
Tabel 4.8 Hubungan variabel-variabel prediktor terhadap kadar serum progesteron pada subyek Penelitian………..76
Tabel 4.9 Nilai Adjusted R Square dari variabel-variabel prediktor kadar serum Progesteron.……….77
Tabel 4.10 Nilai sensitivitas dan spesifisitas serta cut off point dari pemeriksaan Kadar Serum Progesteron pada defek fase luteal………..79
DAFTAR GRAFIK
Grafik 1 Korelasi antar Peak Systolic Velocity (PSV) Aliran Darah Corpus Luteum dengan
Konsentrasi Serum Progestereon………..60
Grafik 2 Korelasi antar End Diastolic Velocity (EDV) Aliran Darah Corpus Luteum dengan
Konsentrasi Serum Progestereon………..63
Grafik 3 Korelasi antar Pulsatility Index (PI) Aliran Darah Corpus Luteum dengan
Konsentrasi Serum Progestereon………..64
Grafik 4 Korelasi antar Resistance Index (RI) Aliran Darah Corpus Luteum dengan
Konsentrasi Serum Progestereon………..67
Grafik 5 Korelasi antar Corpus Luteum dengan Konsentrasi Serum Progestereon…………...70
Grafik 6 Receiver Operating Characteristic (ROC) dari kadar serum progesterone pada
defek fase luteal………..……….78
Grafik 7 Receiver Operating Characteristic (ROC) dari Peak Systolic Velocity (PSV) pada
defek fase luteal………81
Grafik 8 Receiver Operating Characteristic (ROC) dari End Diastolic Velocity (EDV) pada
defek fase luteal………82
Grafik 9 Receiver Operating Characteristic (ROC) dari Pulsatility Index (PI) pada defek fase
Luteal……….,83
Grafik 10 Receiver Operating Characteristic (ROC) dari Resistance Index (RI) pada defek
DAFTAR SKEMA
Skema 1. KERANGKA TEORI PENELITIAN ...38
Skema 2. ALUR PENELITIAN ...51
DAFTAR SINGKATAN
α-SMA α Smooth Muscle Actin
Ang 1 Angiopoeitin 1
Ang 2 Angiopoeitin 2
HSD Hydroxysteroid Dehydrogenase
BBT Basal Body Temperature
CL Corpus Luteum
COS Controlled Ovarian Stimulation
CTGF Connective Tissue Growth Factor
EDTA Ethylene Diamine Tetraacetic Acid
EDV End Diastolic Velocity
FER fertilitas endokrinologi
FSH Follicle Stimulating Hormone
GH Growth Hormone
GnRH Gonadotrophin Releasing Hormone
HDL High Density Lipoproteinm
IGF-I Insulin Like Growth Factor I
IVF In Vitro Fertilization
LDL Low Density Lipoprotein
LH Luteinizing Hormone
LLC Large Luteal Cells
LPD Luteal Phase Defect
mRNA messenger ribo nucleic acid
OHSS Over Hyper Stimulation Syndrome
PCOS Poly Cistic Ovarium Syndrome
PGE2 Prostaglandin E2
PGI 2 Prostaglandin I2
PI Pulsatility Index
PIBF progesteron induced blocking factor
PSV Peak Systolic Velocity
RI Resistance Index
ROC Receiver Operating Characteristic Curve
StAR Steroidogenic acute regulatory protein
USG Ultasonography
DAFTAR LAMPIRAN
Lampiran 1. LEMBAR INFORMASI PASIEN………..
Lampiran 2. LEMBAR PERSETUJUAN PASIEN………
Lampiran 3. KUESIONER PESERTA PENELITIAN………..
Lampiran 4. PERSETUJUAN DAN PENGESAHAN KOMITE ETIK PENELITIAN………..
CORRELATION BETWEEN CORPUS LUTEUM BLOOD FLOW AND PROGESTERONE SERUM CONCENTRATION IN INFERTILE WOMEN
Boy Rivai Pandapotan Siregar, Binarwan Halim, Muhammad Rusda
Departement of Obstetrics and Gynecology
Medical School, University of Sumatera Utara / H. Adam Malik General Hospital / Sub-Division of Reproduction Technology of IVF, Division of FER,Dept of Obgyn, Medical
School-USU
”Halim Fertility Centre” Medan
ABSTRACT
Objective : The purpose of this study is to assess wether any significant correlation between corpus luteum blood flow and progesterone serum concentration on lutheal phase in infertile women. And to determine which parameter of corpus luteum blood flow would be the best predictor to diagnose the lutheal phase defect, as an alternative diagnostic parameter beside the Progesteron Serum Level.
Study Design : This was an analytic survey study research with cross sectional study design,
which performed in Sub-Division of Reproduction Technology of IVF, Division of FER, Obgyn
Departement ,Medical School-USU “HalimFertility Centre”, Medan, since November 1st 2010
until April 30th 2011. The samples of this study were obtained of all infertile women of
reproductive age (15 - 45 years old) which collected by Consecutive Sampling, who is being
selected according to inclusion and exclusion criteria which came to pursue medical check up, then fulfilled the inclusion criterias and willing to participate on this research. By Correlation Pearson Formula (r = 0.433) from literature, 41 samples were obtained to participate. The 41
samples data which completely collected , composed in a master of tabulation, then
computerized by using Computer Statistic Program. Data presented on average
values (Mean)± standard deviation. The presented data described in a scattered Dot graph form. To assess the significance of the relationship between the two variables were used Pearson
correlation analysis and expressed significant if p value <0.05 and by using the r
value to described the strength of the relationship between the two variables of this study. The relationship would be stronger if closer to the value of +1 or-1. The correlation would be positive (+) if found that one variable is directly proportional to the other variable and would be negative (-) if found that one variable varies inversely with the other variable.
Material and Method: Each respondent who fulfilled the inclusion criteria are given respectively a Basal Body Temperature Chart to record their basal body temperature in the
morning every day for 28 days recorded. Day 14 has been estimated as the lowest
temperature during the menstrual cycle, and declared as the day of ovulation. After ovulation, corpus luteum would be formed and developed then started to produces progesterone. Peak
asked to come and pursue the progesterone serum concentration examination, and then performed ultrasound Transvaginal Power Doppler to assess corpus luteum blood flow (PSV, EDV, PI, RI, Volume Corpus Lutem). Each patient which completely examined were recorde on a medical record ,then the Medical Record data collected until completely 41 samples ,and the data were tabulated , then the tabulated data were examined on Pearson correlation test.
Results : By Pearson correlation test, statistically significant correlation was found between serum level of Progesterone (ng/ml) and Peak Systolic Velocity (PSV) of the corpus luteum (cm/s) with p = 0.000 (p <0.05) and was found a positive correlation with the strength value was moderate with r = 0,567. Was found a significant correlation between serum level of Progesterone (ng/ml) and End Diastolic Velocity (EDV) of the corpus luteum (cm/s) with p = 0.000 (p <0.05) and was found a positive correlation with the strength value was strong with r = 0,604. Was found a significant correlation between serum level of progesterone ( ng / ml) and Pulsatility Index of the Corpus Luteum with p = 0.032 (p <0.05) and found a negative correlation with the strength value was weak with r = -0.332. Was found a significant correlation between serum level of progesterone (ng/ml) and Resistance Index of the corpus luteum with p = 0.002 (p <0.05), and found a negative correlation with the strength value was moderate with r = - 0.463. Was found no significant relationship between serum level of progesterone (ng/ml) and the volume of Corpus Luteum (mm3) with p = 0.992 (p> 0.05), and found a positive correlation with the strength value was very weak with r = 0.002. Retrieved the Pulsatility Index (PI) as the best diagnostic tool in this study. AUC value (AUC = 70.1%) which compared to other predictor variables (diagnostic tools) to predict the luteal phase defect ,with cut off point value was 1.085 with a sensitivity of 73, 3% and a specificity of 66.7%.
Conclusion : There is significant correlation between the Peak Systolic Velocity (PSV) of Corpus luteum blood flow (cm/s) and Progesterone serum concentration (ng/ml) and found a positive correlation with the strength value was moderate. There is significant correlation
between the End Diastolic Velocity (EDV) of Corpus Luteum blood flow (cm/s) and
Progesterone serum concentration (ng/ml) and found a positive correlation with the strength value was strong. There is significant correlation between the Pulsatility Index of Corpus Luteum blood flow and Progesterone Serum Concentration (ng/ml) and found a negative correlation with the strength value was weak. There is significant correlation between the Resistance Index of
Corpus Luteum blood flow and Progesterone Serum Concentrations (ng/ml) and found
negative correlation with the strength value was moderate. There was no significant
correlation between the volume of Corpus Luteum (mm3) and Progesterone Serum
CORRELATION BETWEEN CORPUS LUTEUM BLOOD FLOW AND PROGESTERONE SERUM CONCENTRATION IN INFERTILE WOMEN
Boy Rivai Pandapotan Siregar, Binarwan Halim, Muhammad Rusda
Departement of Obstetrics and Gynecology
Medical School, University of Sumatera Utara / H. Adam Malik General Hospital / Sub-Division of Reproduction Technology of IVF, Division of FER,Dept of Obgyn, Medical
School-USU
”Halim Fertility Centre” Medan
THESIS SUMMARY
INTRODUCTION
Infertility in the clinical sense is defined as an inability of one person or a couple to produce conception after one year of regular having sex without using protection, or a woman's inability to maintain pregnancy until term pregnancy. Forecast found in some literature suggests that the incidence of infertility in the United States the incidence ranges from 10-15%. From some literature, other causes of infertility incidence,such as: Male Factor 30-40%, Ovulation Disorders (Diminished Ovarian Reserve, Polycystic Ovaries, hyperprolactinemia, Dysfunction Thyroid) 15%, 5-10% cervical mucus factor, Tuba adhesions 20%, 10% luteal phase defect, Unknown
10%, Other (autoimmune diseases, tumors / Endocrine, Endometriosis) 1
A woman's menstrual cycle is influenced by many hormones, In the first half of the menstrual cycle, GnRH in the hypothalamus induce the Anterior pituitary to release FSH. This FSH stimulates the maturation of follicles in the ovary (follicular phase), resulting in the synthesis of estrogen hormone in large quantities. The estrogen causes the proliferation of endometrium cells, known as Proliferation in the Endometrium or also known as the follicular phase in ovary. Proliferation phase lasts not fixed, can range from 7 to 21 days. This high estrogen signs the pituitary to release the LH. Estrogen in high quantity on mid-menstrual cycle causes ovulation. And then in the second half of Menstrual Cycle, corpus luteum formed then developed, to synthesize progesterone. Progesterone causes changes in the secretory of endometrium, known as Secretion phase in Endometrium which also known as luteal phase in the ovary. Luteal phase
lasts 14 days and usually remains on the same length.2,21,22
Angiogenesis in the corpus luteum occurrs during the menstrual cycle and is functionally important for the maintenance of early pregnancy. After ovulation, as the luteinizing granulosa cell layer become thicker, the basement membrane that separates the granulosa cell layer from the theca cell layer breaks down. Blood vessels from the Theca interna invaded the cavity of the ruptured follicle and form a network that supplies neovascularization luteal cells. Corpus luteum
flow in the corpus luteum is important for the development itself and the maintenance of luteal function 3,4,5,6,7,8
This neovascularization is essential for the delivery of luteal steroid to the general circulation, as well as for the provision of the circulating substrate, Low Density Lipoprotein,that is used by
luteal cells in the biosynthesis of progesterone (Carr et al,1982). Therefore it is likely that blood
flow to the ovary and to the corpus luteum, may be important in the regulation of the function of the Corpus Luteum. Blood flow to the ovary bearing Corpus Luteum increases three to seven fold during luteal phase and then decreases markedly as the Corpus Luteum regresses
(Niswender et al, 1976).3,4,5,6,7,8 If the corpus luteum does not produce progesterone in sufficient quantities and not on time, then the difficulty arises from multiple interactions of focus-focus on the reproductive cycle.1
Transvaginal colour Power Doppler ultrasound imaging- has been used to determine indices of
echogenicity index and intrafollicular blood flow (Collins et al, 1991) and to evaluate serial
indices of echogenicity, vascularity and blood flow throughout the life span of the corpus luteum
(Bourne et al, 1996). Furthermore, color flow pulsed Doppler has been used to predict a luteal
phase defect (Tinkannen, 1994: Glock and Brumsted, 1995). Previous studies using colour
Power Doppler imaging have measured indices of blood flow in the Ovary and the corpus luteum.3,10,11,14,15,16,17,18,19,20,21,24
Changes in the Corpus luteum blood flow in the luteal phase and close relationship with luteal function are interesting topics to be discussed. Interestingly, luteal blood flow correlated significantly with progesterone serum concentration during mid-luteal phase, and luteal blood flow is significantly lower in women with luteal phase defect than women with normal luteal function, which indicates that the low blood flow to the corpus luteum associated with the incidence of luteal phase defect.12,13
Luteal phase defect is a state of recurrent post-ovulation deficiency to produce progesterone from the corpus luteum that result in infertility and recurrent miscarriage. In these circumstances, the corpus luteum is unable to produce an adequate progesterone, causing disturbances in the endometrium such as unsynchronized endometrium stroma and endometrial glands which builds the endometrium. Which in turn caused the disruption of implantation. So a woman is unable to maintain pregnancy until term pregnancy and resulted in the incidence of recurrent miscarriage.1,2,15,20,21,22
Many clinical trials have been performed to diagnose luteal phase defect and various combinations have been used to investigate this situation, including measurement of Basal Body Temperature Chart, endometrial biopsy, pelvic ultrasound to measure the pre-ovulatory follicle diameter pre-ovulation, serum progesterone levels of mid-luteal phase, luteal phase length. Growing discrepancy in the literature that when should we recommend the most optimal time in the menstrual cycle to obtain sampling to determine the luteal phase defect, varied from between
1 to 2 days before the onset of the next menstrual period, up to 9 days after ovulation. However,
the most optimal time is at Mid luteal phase, ie at 7 days after the LH surge or 7 days before onset of next menstruation. Categorized as luteal phase defect wether found Serum Progesterone Levels <10 ng / ml at 7 days after the LH surge or 7 days before onset of next menstruation.1,2,15,20,21,22
This study focused on Correlations between corpus luteum blood flow and Serum Progesterone Concentration in infertile women by using Power Doppler Transvaginal Ultrasound. Based on the literature, Blood flow in the corpus luteum and serum progesterone concentrations associated with female reproductive function. According to this goal, research was conducted to investigate wether found any correlation between corpus luteum blood flow and Serum Progesterone Concentration in infertile women.
Based on the description of the background above, the research problem can be concluded as follows: Does the corpus luteum blood flow correlated with progesterone serum concentration in the luteal phase of infertile women.
The purpose of this study is to assess wether any significant correlation between corpus luteum blood flow and progesterone serum concentration on lutheal phase in infertile women. And to determine which parameter of corpus luteum blood flow would be the best predictor to diagnose the lutheal phase defect, as an alternative diagnostic parameter beside the Progesteron Serum Level. In particular purposes are to determine the relationship between the volume of the corpus luteum and serum concentrations of progesterone, to determine the relationship between Peak Systolic Velocity (PSV) of corpus luteum blood flow and serum concentrations of progesterone ,to determine the relationship between End Diastolic Velocity (EDV) of corpus luteum blood flow and serum concentrations of progesterone, to determine the relationship between the Pulsatility Index (PI) of corpus luteum blood flow and serum concentrations of progesterone,to determine the relationship between the Resistance Index (RI) of corpus luteum blood flow and progesterone serum concentration in the luteal phase of infertile women. . And to determine which parameter of corpus luteum blood flow would be the best predictor to diagnose the lutheal phase defect, as an alternative diagnostic parameter beside the Progesteron Serum.
This research is expected to gain more knowledge and understanding of the corpus luteum blood flow and its effect on the production of progesterone in the luteal phase of infertile women. Transvaginal colour Power Doppler Ultrasound imaging examination was able to help to diagnose blood flow of the corpus luteum in the luteal phase of infertile women and could be an alternative non-invasive diagnostic to diagnose the Luteal Phase Defect beside The examination of Progesterone serum concentration.
MATERIAL AND METHODS
This was an analytic survey study research with cross sectional study design, which performed in
Sub-Division of Reproduction Technology of IVF, Division of FER, Obgyn Departement
,Medical School-USU “Halim Fertility Centre”, Medan, since November 1st 2010 until April
30th 2011. The samples of this study were obtained of all infertile women of reproductive age (15
- 45 years old) which collected by Consecutive Sampling, who is being selected according to
inclusion and exclusion criteria which came to pursue medical check up, then fulfilled the inclusion criterias and willing to participate on this research.
Each respondent who fulfilled the inclusion criteria are given respectively a Basal Body
Temperature Chart to record their basal body temperature in the morning every day for 28 days
recorded. Day 14 has been estimated as the lowest temperature during the menstrual
cycle, and declared as the day of ovulation. After ovulation, corpus luteum would be formed and developed then started to produces progesterone. Peak of the luteal phase has been estimated on 7 days after ovulation. On day 21 patients were asked to come and pursue the progesterone
serum concentration examination, and then performed ultrasound Transvaginal Power Doppler to assess corpus luteum blood flow (PSV, EDV, PI, RI,
Volume Corpus Lutem). Each patient which completely examined were recorde on a medical record ,then the Medical Record data collected until completely 41 samples ,and the data were tabulated , then the tabulated data were examined on Pearson correlation test.
By Correlation Pearson Formula (r = 0.433) from literature, 41 samples were obtained to participate. The 41 samples data which completely collected , composed in a master of tabulation, then computerized by using Computer Statistic Program. Data presented on average values (Mean)± standard deviation. The presented data described in a scattered Dot graph form. To assess the significance of the relationship between the two variables were used Pearson
correlation analysis and expressed significant if p value < 0.05 and by using the r
RESULTS
After 6 months duration of this study, from November 1st, 2010 to April 30th, 2011, which
[image:35.612.101.509.220.366.2]performed at Sub-Division of Reproductive Technology IVF,Division of FER, Department of Obgyn FK-USU "Halim Fertility Centre" obtained 42 infertile women who admitted to performed examination, who fulfilled the inclusion criteria .
Table 4.1 . Correlation between Peak Systolic Velocity (PSV) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
Mean SD P r
Peak Systolic Velocity
(PSV) (cm/s)
12.75 7.30 0.000* 0.567*
Serum Progesteron (ng/ml)
13.06 4.77
*Pearson correlation test
Graphic 1. Correlation between Peak Systolic Velocity (PSV) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
From the scattered dot graph above described a positive correlation between the Progesterone serum concentration and Peak Systolic Velocity (PSV) of the corpus luteum blood flow with the strength value is moderate correlation r = 0.567.
Table 4.2 Correlation between End Diastolic Velocity (EDV) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
Mean SD p R
End Diastolic Velocity
(EDV)(cm/s)
4.54 3.95 0.000* 0.604*
Serum Progesteron (ng/ml)
13.06 4.77
*Pearson correlation test
The Average level of Progesterone serum concentration of the participants on this study is 13.06 ± 4.77 ng / ml with Average End Diastolic Velocity (EDV) of the Corpus Luteum blood flow of the participants of this study is 4.54 ± 3.95 cm/s. By Pearson correlation test, found statistically significant correlation between Progesterone serum concentration and End Diastolic Velocity (EDV) of the corpus luteum blood flow with p = 0.000 (p <0.05) and found a positive correlation between Progesterone serum concentration and End Diastolic Velocity ( EDV) of the corpus luteum blood flow with the strength value is Strong, with r = 0.604.
Graphic 2. Correlation between End Diastolic Velocity (EDV) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
From the scattered dot graph above described a positive correlation between the Progesterone serum concentration and End Diastolic Velocity (EDV) of the corpus luteum blood flow with the strength value is Strong correlation r = 0.604.
.
s
Table 4.3Correlation between Pulsatility Index (PI) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
Mean SD P r
Pulsatility Index (PI) 1.12 0.51 0.032* - 0.332*
Serum Progesteron (ng/ml)
13.06 4.77
*Pearson correlation test
Graphic 3. Correlation between Pulsatility Index (PI) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
From the scattered dot graph above described a negative correlation between the Progesterone serum concentration and Pulsatility Index (PI) of the corpus luteum blood flow with the strength value is Weak correlation r = - 0.332
Table 4.4Correlation between Resistance Index (RI) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
Mean SD P R
Resistance Index (RI) 0.71 0.36 0.005* - 0.423*
Serum Progesteron (ng/ml)
13.07 4.77
*Pearson correlation test
Graphic 4. Correlation between Resistance Index (RI) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
From the scattered dot graph above described a negative correlation between the Progesterone serum concentration and Resistance Index (RI) of the corpus luteum blood flow with the strength value is Moderate correlation r = - 0.423
Table 4.5Correlation between Volume Corpus Luteum and progesterone serum concentration in the mid-luteal phase
Mean SD P r
Volume corpus luteum (cm3)
7.13 4.48 0.992* 0.002*
Serum Progesterone (ng/ml)
13.14 4.65
*Pearson correlation test
Graphic 5.Correlation between Volume Corpus Luteum and progesterone serum concentration in the mid-luteal phase
From the scattered dot graph above described a positive correlation between the Progesterone serum concentration and Volume corpus luteum with the strength value is very weak correlation r = 0.002
DISCUSSION
Corpus luteum becomes highly vascularized within a few days after ovulation so that, on a
tissue-to-weight basis, blood flow to the corpus luteum is among the greatest of any tissue in the body (Abdul-Karim and Bruce, 1973). This increased vascularity, in addition to providing a conduit for the delivery of luteal steroids to the general circulation, it also necessary for the provision of the cholesterol substrate in the form of Low Density Lipoprotein, for progesterone biosynthesis (Carr et al, 1982). Therefore, it seems likely that blood flow to the ovary and the corpus luteum
may be important in regulating the function of the corpus luteum.3
Progesterone serum concentration peaked 6 to 8 days before the start of menstruation. The early luteal stage is characterized by the rapid proliferation of endothelial cells and invasion of capillaries from the cores of the luteal tissue infoldings, which contain connective tissue and blood vessels derived from the theca into the peripheral areas of the infoldings, which contain
granulosa-derived luteal cells (Gaede et al. 1985). The mid-luteal stage is characterized by the
formation of a dense microvascular network composed primarily of capillaries. The late luteal stage is characterized by the regression of the capillaries, a relative increase in connective tissue, an increased abundant of larger microvessels, and a regression and loss of luteal parenchymal
cells(Azmi dan O’Shea, 1984; Jablonka Shariff dkk., 1993).3
In research of Bau and Bajo in Madrid, Spain in 2001, found the serum levels of progesterone
was significantly lower in women with luteal phase defect than women with normal cycles. And the length of the luteal phase is found shorter in women with luteal phase defect than women
with normal cycles.16
Kupesic and Kurjak Research in Zagreb, Croatia, 1996, found the average progesterone serum level was significantly lower in women with luteal phase defect compared to the control group ( p < 0.01 ).9,25
Correlation between Peak Systolic Velocity (PSV) of Corpus Luteum blood flow and progesterone serum concentration in the mid-luteal phase
Miyazaki et al, 1998, in Japan in their research, PSV found peaked at 8-6 days before the onset of the next menstrual period and declined until the late luteal phase. Serum concentrations of progesterone showed the same changes, increased from 12-16 days before the start of the next menstrual period and peaked at 6-8 days before onset of next menstruation. Although the PSV did not correlate with serum concentrations of progesterone in their study, but it showed the same pattern of changes in progesterone serum concentrations in accordance with a previous
study conducted by Bourne et al., 1996.3
Bourne et al, 1996, showed a close relationship between the PSV of blood flow surrounding the
Niswender et al, 1976 showed that blood flow to the ovary and the number and size of luteal cells may be important in the regulation of progesterone production by the ovary. Blood flow to the ovary bearing corpus luteum increases three to sevenfold during the luteal phase and then
decreases markedly as the corpus luteum regresses.3,7,8
Hong-Ning Xie et al, Japan. In 2001 revealed that the blood flow of intra-Ovarial clearly show maximum velocity and low resistance index in the mid-luteal phase in normal menstrual cycle, suggesting that the blood vessels of the corpus luteum has a minimum flow of Resistance Index because they are maximally dilated, so it is not optimal for vasomotor motion. The same pattern was found in luteal blood flow and progesterone levels during developing corpus luteum, indicating that the corpus luteum of adequate vascularization is a physiological need for adequate luteal function. This research indicates that the increase in luteal blood flow is the impact of vascular dilatation in early luteal phase. PSV was found positively correlated with serum concentrations of progesterone. This supports the concept that luteal blood flow velocity is a
complementary parameter that describes the luteal function in infertility.19
Relationship between PSV of Corpus Luteum blood flow and luteal phase deficiency, Bau and
Bajo ,Madrid, Spain in 2001, found that the PSV in mid-luteal phase of women with luteal phase defect is lower than PSV in women with normal cycles. And found a significant correlation between PSV and progesterone serum concentration in women with luteal phase defect ( r = 0,36 ).16
On this present study, found a significant correlation between the Peak Systolic Velocity (PSV) of Corpus luteum blood flow (cm/s) and Progesterone serum concentration (ng/ml) and found a positive correlation with the strength value was moderate.
Correlation between End Diastolic Velocity (EDV) of corpus luteum blood flow and progesterone serum concentration in the mid-luteal phase
Ottander et al., Sweden in 2004 showed that the End Diastolic Velocity (EDV) decreased significantly at the end-luteal phase than mid-luteal phase. It also found in the pattern of changes
of PSV, where PSV showed a similar pattern of changes with the pattern of change of EDV.10
Relationship of EDV and luteal phase deficiency, Bau and Bajo in Madrid, Spain 2001, On this
research found no difference between end diastolic blood flow velocity intra ovarial in women
with luteal phase defect than women with normal ovulatoar cycle.16
On this present study, found a significant correlation between
Correlation between Pulsatility Index (PI) of corpus luteum blood flow with progesterone serum concentration in the mid-luteal phase
Miyazaki et al. In Japan, 1998 in his research found that the Pulsatility Index (PI) of ovarian artery reaches its nadir in the mid-luteal phase (3-8 days prior to the next menstrual cycle). Progesterone serum concentration showed similar changes, increased from 12-16 days before the start of the next menstrual period and peaked on 6-8 days before onset of next menstruation. In this study, intra-luteal PI are found to be associated with serum progesterone. Progesterone peaked in mid-luteal phase (8-6 days before onset of next menstruation), while intra-luteal PI began to decreased in the early luteal phase (11-9 days before the start of the next menstrual period) and then increased until the beginning of the next menstrual period. The difference between the maximum period of progesterone serum concentrations with lowest PI period point showing the fact that the increase in circulating hormone is inversely proportional to
the increase in corpus luteum of structural vascularization.3
Hata et al, 1990; Glock et al, 1995suggest that the low PI values associated with lower RI. The blood supply to the ovary bearing corpus luteum increased during the luteal phase, especially in the mid-luteal phase in line with increased consumption of Low-Density Lipoprotein to the luteal
cells to produce progesterone in the corpus luteum.3
Tinkanen et al., Finland, 1994in her research found no significant difference in terms of intra-Ovarial Pulsatility Index (PI) with Progesterone Serum Levels. However, inadequate number of patients and insuficient methods used for evaluation of luteal function in this study, have become limitations in this study.9
On this present study, found a significant correlation between the Pulsatility Index of
Corpus Luteum blood flow and Progesterone Serum Concentration (ng/ml) and found a
negative correlation with the strength value was weak.
Correlation between Resistance Index (RI) of Corpus Luteum blood flow and Progesterone serum concentration in the Mid-Luteal Phase
In the study ofKupesic and Kurjak in Croatia in 1996, their research found the lowest RI value
at the mid-luteal phase, which then increased to higher values in the late luteal phase. The average progesterone level was significantly lower (P <0.001) in the luteal phase defect group
than the control group.9,25
Glock and Brunsted, 1995, showed a significant relationship between intra Ovarial -RI and
Plasma Levels of progesterone in the luteal phase. Similar to the research of Kupesic and Kurjak
detected in the mid-luteal phase in line with the peak of corpus luteum Angiogenesis. Increased
RI is shown in the late luteal phase as the regression of the corpus luteum.3,14
In the study of Tamura et al. in Japan in 2008, found that luteal RI in the mid-luteal phase in
women with luteal phase defect increased significantly compared with women with normal luteal function. Luteal RI was significantly correlated with progesterone serum concentrations in the mid-luteal phase. In this study, shows that the luteal RI decreased during the early luteal phase and increased during the regression phase. Furthermore, this study showed high luteal RI and low progesterone serum levels are found during the luteal phase. In fact, angiogenesis is essential for corpus luteum development and maintenance of luteal function. These findings indicate that blood flow is an important factor to regulate luteal function. Therefore, showing that the luteal
phase defect is caused by defective regulation of blood flow during mid-luteal luteal phase.11
Study by Takasaki et al. in Japan in 2009 that conducts research on the corpus luteum blood
flow associated with luteal function found a significant negative correlation between corpus
luteum RI with progesterone serum concentrations during mid-luteal phase.17
Relationship between RI and luteal phase defect, both previous studies and the study of Takasaki
et al, Japan,2009 support that the luteal phase defect associated with the presence of high RI in corpus luteum because luteal RI in women with luteal phase defects during mid-luteal phase increased significantly compared to women with normal luteal function and corpus luteum RI negatively correlated with progesterone serum concentrations during the Mid-luteal phase on
women with normal cycles. 17
On this present study, found a significant correlation between the Resistance Index of
Corpus Luteum blood flow and Progesterone Serum Concentrations (ng/ml) and found
negative correlation with the strength value was moderate..
Correlation between the Volume of Corpus Luteum and Progesterone Serum Concentration in the Mid-Luteal Phase
Miyazaki et al., 1998 in Japan showed the corpus luteum image with Doppler transvaginal ultrasound imaging during the luteal phase. Areas that seen increased vascularity in the time of periovulation to mid-luteal phase and declined until the next menstrual period. Volume of Corpus Luteum showed the same pattern as changes in Progesteron serum concentrations. Although the changes in volume corpus luteum is proportional to the change of Progesterone Serum Concentrations, but there is no significant correlation between the volume of the corpus
luteum and Serum Concentrations of Progesterone.3
Jablonka Shariff et al., 1993 on their research found that the rapid growth of luteal
Bruce and Moor, 1976;. Niswender et al, 1976 found the luteal phase blood flow increased
dramatically in relation to the increase in corpus luteum tissue growth.3,7,8
Bourne et al, 1996 found a significant correlation between the size of the corpus luteum with
progesterone production, shown in his research.3,13
Jokubkiene et al., Sweden 2006, in his study he found there was no significant relationship between volume corpus luteum on day-7 and progesterone level on day-7 after ovulation. The study found no correlation between serum progesterone levels with blood flow to the corpus luteum in the mid-luteal phase. Progestreron level is a description of the corpus luteum function, but blood flow does not depict progesterone production in the corpus luteum. Corpus luteum highest volume found in the early luteal phase and decreased significantly at the end of the luteal phase.24
Furthermore, the study of Singh et al 1997 found that the size of luteal cell increases during the
formation of the corpus luteum and decreases during the regression of the corpus luteum.3
On this present study, found no significant correlation between the Volume of Corpus Luteum (mm3) and Progesterone Serum Concentration and found a positive correlation with the strength value was very weak.
CONCLUSION
Based on the purpose of this study, results and discussion of this study, it can be concluded that :
There is significant correlation between the Peak Systolic Velocity (PSV) of Corpus luteum
blood flow (cm/s) and Progesterone serum concentration (ng/ml) and found a positive
correlation with the strength value was moderate. There is significant correlation between the End Diastolic Velocity (EDV) of Corpus Luteum blood flow (cm/s) and Progesterone serum concentration (ng/ml) and found a positive correlation with the strength value was strong. There
is significant correlation between the Pulsatility Index of Corpus Luteum blood flow
and Progesterone Serum Concentration (ng/ml) and found a negative correlation with the strength value was weak. There is significant correlation between the Resistance Index of
Corpus Luteum blood flow and Progesterone Serum Concentrations (ng/ml) and found
negative correlation with the strength value was moderate. There was no significant
correlation between the volume of Corpus Luteum (mm3) and Progesterone Serum
Concentrations and found a positive correlation with the strength value was very weak. Retrieved the Pulsatility Index (PI) as the best diagnostic tool in this study. AUC value (AUC = 70.1%) which compared to other predictor variables (diagnostic tools) to predict the luteal phase defect ,with cut off point value was 1.085 with a sensitivity of 73, 3% and a specificity of 66.7%.
RECOMMENDATION
REFERENCES
1. Jacqueline P, Thomas N D, “Infertility due to Luteal Phase Defects : Option in
Diagnosis, and Treatment with Bio-Identical Progesterone”
2. Baziad Ali, “ Endokrinologi GinekologiEdisi Ketiga Bab 8 defek Fase Luteal “ Media
Auscaulapius. Fakultas Kedokteran Universitas Indonesia, Jakarta, 2008: 101-4
3. Miyazaki T, Tanaka M, Miyakoshi K, Minegishi K, Kasai K, Yoshimura Y: “Power and
colour Doppler ultrasonography for the evaluation of the vasculature of the human corpus luteum”.Hum Reprod 1998, 13 : 2836-2841.
4. Hazzard TM, Stouffer RL: “Angiogenesis in ovarian follicular and luteal development”
. Baillieres Best Pract Res Clin Obstet Gynaecol 2000, 14 : 883-900
5. Sugino N, Suzuki T, Sakata A, Miwa I, Asada H, Taketani T, Yamagata Y, Tamura H:
“Angiogenesis in the human corpus luteum : Changes in expression of angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancy”. J Clin Endocrinal Metab 2005, 90:6141-6148
6. Sugino N, Matsuoka A, Taniguchi K, Tamura H: “Angiogenesis in the human corpus
luteum” .Reprod Med Biol 2008, 7 : 91-103.
7. Niswender GD, Reimers TJ, Diekman MA, Nett TM: “Blood flow: a mediator of
ovarian function”. Biol Reprod 1976, 4 : 64-81.
8. Niswender GD, Juengel JL, Silva PJ, Rollyson MK, McIntosh EW “Mechanisms
Controlling the Function and Life Span of the Corpus Luteum” .Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado. Physiological Reviews, vol 80 ,No 1, January 2000, pp 1-29
9. Kupesic S, Kurjak A: “The assessment of normal and abnormal luteal function by
transvaginal color Doppler sonography”.Eur J Obstet Gynecol Reprod Biol 1997, 72 : 83-87.
10.Ottander U, Solensten NG, Bergh A, Olofsson Jl: “Intra-ovarian blood flow measured
with color Doppler ultrasonography inversely correlates with vascular density in the human corpus luteum of the menstrual cycle”. Fertil Steril 2004, 8 : 154-159.
11.Tamura H, Takasaki A, Taniguchi K, Matsuoka A, Shimamura K, Sugino N: “Changes
in blood flow Impedance of the human corpus luteum throughout the luteal phase and during early pregnancy”.Fertile Steril 2008, 90 : 2334-2339.
12.Alcazar JL, Laparte C, Lopez-Garcia G: “Corpus luteum blood flow in abnormal early
13.Bourne TH, Hagstrom H, Hahlin M, Josefsson B, Granberg S, Hellberg P, Hamberger L,
Collins WP: “Ultrasound studies of vascular and morphological changes in the human
corpus luteum during the menstrual cycle”. Fertil Steril 1996, 65 : 753-758.
14.Glock JL, Brumsted JR: “Color flow pulsed Doppler ultrasound in diagnosing luteal
phase defect “. Fertil Steril 1996, 64 : 500-504.
15.Kalogirou D, Antoniou G, Botsis D, Kontoravdis A, Vitoratos N, Giannikos :
“Transvaginal Doppler ultrasound with color flow imaging in the diagnosis of luteal phase defect(LPD)”. Clin Exp Obstet Gynecol 1997,24 : 95-97.
16.Bau MLT, Bajo JM: “Doppler study of arterial and venous intraovarian blood flow in
stimulated cycles”.Ultrasound Obstet Gynecol 2001, 18 : 505-510.
17.Takasaki A,et al: : ” Luteal Blo
