Perbandingan Efektifitas dan Efek Samping Pemakaian Metformin XR dan Metformin IR dalam Pengobatan PCOS yang Resisten terhadap Clomiphene Citrate

Perbandingan Efektifitas dan Efek Samping

Pemakaian Metformin XR dan Metformin IR

dalam Pengobatan PCOS yang Resisten

terhadap Clomiphene Citrate

TESIS

OLEH :

HEDY TAN

DEPARTEMEN OBSTETRI DAN GINEKOLOGI

FAKULTAS KEDOKTERAN UNIVERSITAS SUMATERA UTARA

RSUP. H. ADAM MALIK

MEDAN

2011

PENELITIAN INI DI BAWAH BIMBINGAN TIM-5

Pembimbing : Dr. Binarwan Halim, Sp.OG.K

Dr. Yostoto B. Kaban, Sp.OG.K

Penyanggah : Dr. Herbert Sihite, Sp.OG

Dr. M. Fidel Ganis Siregar, Sp.OG

Prof. Dr. M.Fauzie Sahil, Sp.OG.K

Diajukan untuk melengkapi tugas-tugas dan memenuhi

salah satu syarat untuk menyelesaikan program adaptasi

dokter spesialis

i   

KATA PENGANTAR

Segala Puji dan Syukur saya panjatkan kepada Tuhan Yang Maha Kuasa, karena kasih

dan karunia-Nya maka penulisan tesis ini dapat diselesaikan.

Tesis ini disusun untuk melengkapi tugas-tugas dan memenuhi salah satu syarat untuk

menyelesaikan program adaptasi dokter spesialis Obstetri dan Ginekologi lulusan luar

negeri. Sebagai manusia biasa, saya menyadari bahwa tesis ini banyak kekurangannya

dan masih jauh dari sempurna, namun demikian besar harapan saya kiranya tulisan

sederhana ini dapat bermanfaat dalam menambah perbendaharaan bacaan khususnya

tentang :

“

PERBANDINGAN EFEKTIFITAS DAN EFEK SAMPING PEMAKAIAN

METFORMIN XR DAN METFORMIN IR DALAM PENGOBATAN PCOS

YANG RESISTEN TERHADAP CLOMIPHENE CITRATE ”

Dengan selesainya laporan penelitian ini, perkenankanlah saya menyampaikan rasa

terima kasih dan penghargaan yang setinggi-tingginya kepada yang terhormat :

1.

Rektor Universitas Sumatera Utara dan Dekan Fakultas Kedokteran Universitas

Sumatera Utara, yang telah memberikan kesempatan kepada saya untuk mengikuti

Program Adaptasi Dokter Spesialis Obstetri dan Ginekologi lulusan luar negeri di

Fakultas Kedokteran USU Medan.

2.

Prof. dr. Delfi Lutan, MSc, SpOG.K, Ketua Departemen Obstetri dan Ginekologi

FK-USU Medan ; dr. M. Fidel. G. Siregar, SpOG, Sekretaris Departemen Obstetri

dan Ginekologi FK-USU Medan ; dr. Henry Salim Siregar, SpOG.K, Ketua

Program Studi Dokter Spesialis Obstetri dan Ginekologi FK-USU Medan ; dr. M.

Riza. Z. Tala, SpOG.K, Sekretaris Program Studi Dokter Spesialis Obstetri dan

Ginekologi FK-USU Medan ; Prof. dr. R. Haryono. R. Roeshadi, SpOG.K ; Prof.

dr. Hamonangan Hutapea, SpOG.K ; Prof. DR. dr. M. Thamrin Tanjung, SpOG.K ;

ii   

Prof. dr. T. M. Hanafiah, SpOG.K ; Prof. dr. Budi R. Hadibroto, SpOG.K ; dan

Prof. dr. Daulat H. Sibuea, SpOG.K ; Prof. dr. M. Fauzie Sahil, Sp.OG.K yang telah

bersama-sama berkenan menerima saya untuk mengikuti program adaptasi dokter

spesialis lulusan luar negeri di Departemen Obstetri dan Ginekologi.

3.

Prof. dr. M. Fauzie Sahil, SpOG.K, ketua tim pelaksana adaptasi dokter spesialis

obstetri dan ginekologi lulusan luar negeri; dr. Muhammad Rusda, SpOG.K,

sekretaris tim pelaksana adaptasi dokter spesialis obstetri dan ginekologi lulusan

luar negeri; Prof. dr. R. Haryono. R. Roeshadi, SpOG.K ; Prof. dr. Delfi Lutan,

MSc, SpOG.K ; dr. Deri Edianto SpOG.K, anggota tim pelaksana adaptasi dokter

spesialis obstetri dan ginekologi lulusan luar negeri selama saya menjalani masa

adaptasi, yang telah banyak mengayomi, membimbing dan memberikan

nasehat-nasehat yang bermanfaat kepada saya dalam menghadapi masa-masa sulit selama

adaptasi.

4.

dr. Ichwanul Adenin, SpOG.K selaku Kepala Sub Divisi Fertilitas Endrokrinologi

dan Reproduksi atas kesempatan yang diberikan kepada saya untuk melakukan

penelitian ini.

5.

dr. Binarwan Halim, SpOG.K dan dr. Yostoto B Kaban, SpOG.K selaku

pembimbing utama penelitian ini yang dengan rela dan dengan penuh kesabaran,

yang telah meluangkan waktunya yang sangat berharga untuk membimbing,

memeriksa dan melengkapi penulisan tesis saya ini dari awal hingga selesai.

6.

dr. Herbert Sihite, SpOG ; dr. M. Fidel. G. Siregar, SpOG ; dan Prof. dr. M. Fauzie

Sahil, SpOG.K, selaku penyanggah dan nara sumber dalam penulisan tesis ini, yang

telah banyak memberikan bimbingan dan masukan dalam perbaikan tesis ini.

7.

Prof. dr. Daulat H. Sibuea, SpOG.K, selaku pembimbing referat mini fetomaternal

iii   

Sarma N Lumbanraja, SpOG.K, selaku pembimbing referat mini fetomaternal saya

yang berjudul

”Pemakaian Low-molecular-weight Heparin selama Kehamilan

dan Nifas“

; dr. Aswar Aboet, SpOG.K selaku pembimbing referat mini Fertilitas

Endokrinologi dan Reproduksi saya yang berjudul

”Keguguran Kahamilan

Berulang”

dan dr. Hj. Sarah Dina, SpOG.K selaku pembimbing referat mini

Onkologi saya yang berjudul

”Human Papillomavirus (HPV) dan Vaksinasi”

8.

Kepada dr. Surya Dharma, M.Kes, yang telah meluangkan waktu dan pikiran untuk

membimbing saya dalam penyelesaian uji statistik tesis ini.

9.

Seluruh Staf Pengajar di Departemen Obstetri dan Ginekologi FK-USU Medan,

yang secara langsung maupun tidak langsung telah banyak membimbing dan

mendidik saya sejak awal hingga akhir program adaptasi. Semoga Yang Maha

Pengasih membalas budi baik guru-guru saya tersebut.

10.

Direktur RSUP. H. Adam Malik Medan beserta staf yang telah memberikan

kesempatan dan sarana kepada saya untuk bekerja selama mengikuti program

adaptasi di Departemen Obstetri dan Ginekologi.

11.

Direktur RSUD. Dr. Pirngadi Medan ; Kepala SMF Obstetri dan Ginekologi

RSUD. Dr. Pirngadi Medan beserta staf yang telah memberikan kesempatan dan

sarana kepada saya untuk bekerja selama mengikuti program adaptasi di

Departemen Obstetri dan Ginekologi.

12.

Direktur RS. PTPN 2 Tembakau Deli ; dr. Sofian Abdul Ilah, SpOG dan dr.

Nazaruddin Jaffar, SpOG.K beserta staf yang telah memberikan kesempatan dan

sarana kepada saya untuk bekerja selama bertugas di Rumah Sakit tersebut.

13.

Direktur RS Haji Mina Medan, beserta staf yang telah memberikan kesempatan

iv   

14.

Ka. Rumkit Tk II Putri Hijau KESDAM I/BB & Ka. SMF OBSGYN Mayor. CKM.

dr. Gunawan Rusuldi, SpOG beserta staf yang telah memberikan kesempatan dan

sarana kepada saya untuk bekerja selama bertugas di Rumah Sakit tersebut.

15.

Direktur RSU Sundari Medan, beserta staf yang telah memberi kesempatan dan

sarana kepada saya untuk bekerja selama bertugas di Rumah Sakit tersebut.

16.

Direktur RSU HKBP Balige, beserta staf yang telah memberikan kesempatan kerja

dan bantuan moril selama saya bertugas di rumah sakit tersebut.

17.

Kepada teman-teman sejawat saya yang telah menyelesaikan Program Pendidikan

Dokter Spesialis Obstetri dan Ginekologi : dr. Ronny. P. Bangun, SpOG, dr. Siti

Sylvia. S, SpOG, dr. Gorga. I. V. W. Udjung, SpOG, dr. Ilham S Lubis, SpOG, dr.

Anggia Lubis, SpOG, dr. Maya Hasmita, SpOG, dr. M. Ikhwan, SpOG, dr. Edward

Muldjadi, SpOG, dr. Zilly Adein, SpOG, dr. Lili kuswani, SpOG, dr. Ari. A. Lbs

SpOG, dr. T. Jeffrey. A, SpOG, dr. M. Rizky Yaznil, SpOG, dr. Made Surya.K,

SpOG, dr. M. Jusuf. R SpOG, dr. Sri Jauhara Laily, SpOG, dr. G. Joshimin F,

SpOG, dr. Alfian. Z. Srg, SpOG, dr. Firman Alamsyah, SpOG, dr. Aidil Akbar,

Sp.OG, dr. Andri. P. Aswar, SpOG, dr Errol Hamzah, SpOG terima kasih banyak

atas segala bantuan dan dukungannya yang telah diberikan selama ini.

18.

Kepada teman-teman sejawat saya PPDS Obstetri dan Ginekologi : dr. Riza. H. Nst,

dr. Boy. R. P. Srg, dr. Hatsari. M. P. S.S, dr. Rizka Heriansyah, dr. Reynanta dr. T.

Johan. A, dr. Elvira. M. S, dr. Yuri Andriansyah, dr. Tigor Hasugian, dr. Riske Eka

Putri, dr. Ulfa WK, dr. Hendryadi, dr. Heika. N. Silitonga, dr. Irwansyah. P, dr. Ali

Akbar. Hsb, dr. Ismail Usman, dr. Arjuna. S, dr. Janwar. S, dr. M. Yusuf, dr. Meity

Elvira, dr. Hendri Ginting, dr. Dany Ariyani, dr. Fatin Atifa, dr. Eka Handayani, dr.

Hendri Gunawan, dr. Ferdiansyah Putra, dr. Kiko Marpaung, dr. M. Wahyu

Wibowo, dr. Novrial, dr. Morel Sembiring, dr. Sri Damayana, dr. Yudha Sadewo,

v   

dr. M. Arif Siregar, dr. Pantas Saroha Siburian, dr. Abdur Rohim Lubis, dr. Hotbin

Purba, dr. Hiro HD Nasution, dr. Anindita Novina, dr. Nureliani Amni, dr. Liza

Marosa, dr. Julita A Nasution, dr. Aries Misrawani, dr. Ivo F Canitri, dr. M Rizky

Pranata, dr. Ray Barus, dr. Robby. P, dr Edward S Manurung, Edy Rizaldy, Erwin

E Saputra, dr. Rizal Sangadji, dr. Ricca P Rahim, dr. Ika Sulaika, dr. Fifianti Putri

Adela, dr. Chandran F Saragih, dr. Dona Wirniaty, dr. Apriza Prahatama, dr Hilma

Putri Lubis, dr. Rahmanita Sinaga, dr. Muhammad Dezarino, dr. Alfred Hara

Sinuhaji, dr. Ninong Ade Putri, dr. M Faisal Fahmi, dr. Renny Anggraini, dr.

Yasmien Hasby, dr. Johan Ricardo, dr. Arvitamurianty T Lubis, dr. Juhriyani M

Lubis, dr. Hermima Nurul A, dr. Meifi Elfira, , dr. Bandini, dr. Hendrik A Tarigan

Tua, dr. Dina K Wiratma, dr. Dewi Andriyati, dr. Aliya Hanifa, dr. Daniel Hendra

Simbolon, dr. Servin Pandu Djagadinata, dr Yufi Permana, dr. Trishna, dr. Renny

Junitasari, dr. Tri Sugeng Hariadi, dr. Masithah Thaharuddin, dr. Jesurun. B. D.

Hutabarat, dr. Adrian Octara Sinuhaji, dr. Eva Maya Puspita, dr. M Gamal Darus,

dr. Nafon Zaitun, dr. Rizal K Aritonang, dr. Obed P A Simatupang, dr. Aurora M

Farrah, dr. Indra Setiawan, dr. M Wahyu Utomo, dr. Eunike W Zega dan seluruh

PPDS obstetri & Ginekologi FK-USU yang tidak dapat saya ucapkan satu per satu,

saya menyampaikan terima kasih atas dukungan dan bantuan yang diberikan selama

penelitian dan pembuatan tesis saya ini.

19.

Dokter Muda, Bidan, Paramedis, karyawan / karyawati, serta para pasien di

Departemen Obstetri dan Ginekologi FK USU / RSUP. H. Adam Malik – RSU. Dr.

Pirngadi Medan, RS Tembakau Deli, RS Haji Mina, Rumkit Kesdam, RS Sundari,

RS HKBP Balige yang daripadanya saya banyak memperoleh pengetahuan, terima

kasih atas kerja sama dan saling pengertian yang diberikan kepada saya sehingga

dapat sampai pada akhir program adaptasi ini.

Sembah sujud, hormat dan terima kasih yang tidak terhingga saya sampaikan kepada

kedua Orang Tua saya yang tersayang ayahanda,

Tan A Heng (Alm)

dan Ibunda,

Tan Sie

Moy

yang telah membesarkan, membimbing, mendoakan, serta mendidik saya dengan

vi   

menjalani hidup serta memberikan motivasi dan semangat kepada saya selama mengikuti

pendidikan ini.

Buat mertua saya yang tercinta

dr. H. Raja Imran Ritonga, MsC

dan

dr. Rosa Dalima,

terima kasih yang tidak terhingga saya sampaikan atas dukungan baik dari segi moril

maupun materiil kepada saya sehingga saya dapat menyelesaikan program adaptasi ini.

Buat istriku yang tercinta dan kukasihi

dr. Imelda Liana Ritonga, SkP, MPD, MN

, tiada

kata lain yang bisa saya sampaikan selain terima kasih yang sebesar-besarnya atas

pengertian, kesabaran, dorongan semangat, pengorbanan dan doa yang diberikan kepada

saya sehingga saya dapat menyelesaikan program adaptasi ini.

Anak-anak ku yang tercinta dan kukasihi

Nathasya Veronica Winardi, Josephine

Lidwina Winardi, Gabriella Valentina Winardi

, tiada kata lain yang bisa papa

sampaikan selain terima kasih yang sebesar-besarnya atas cinta kasih, pengertian,

kesabaran, dorongan semangat, pengorbanan dan doa yang diberikan kepada papa

sehingga papa dapat menyelesaikan program adaptasi ini. Semoga apa yang telah papa

lakukan dapat menjadi teladan dan semangat bagi ananda untuk mencapai cita-cita yang

lebih baik lagi

Kepada seluruh keluarga yang tidak dapat saya sebutkan satu persatu, yang secara langsung

maupun tidak langsung telah banyak memberikan bantuan, baik moril maupun materiil,

saya ucapkan terima kasih yang sebesar-besarnya.

Semoga Tuhan Yang Maha Esa senantiasa melimpahkan rahmat dan berkahNya serta

dibukakan pintu ilmu kepada kita semua.

Amin

Medan, Oktober 2011

vii   

DAFTAR ISI

Halaman

KATA PENGANTAR……… i

DAFTAR ISI……….. vii

DAFTAR GAMBAR……….. x

DAFTAR TABEL……… xi

ABSTRAK………... xii

BAB I PENDAHULUAN

1.1

Latar Belakang………

1

1.2

Rumusan Masalah………...………

3

1.3

Hipotesis………...……….. 3

1.4

Tujuan Penelitian…...……….

3

1.4.1

Tujuan Umum………...

3

1.4.2

Tujuan Khusus………...

3

1.5

Manfaat Penelitian……….

4

BAB II TINJAUAN KEPUSTAKAAN

2.1

Polycystic Ovary Syndrome ……….

5

2.1.1

Definisi ……….. 5

2.1.2

Prevalensi ……….. 7

2.1.3

Etiologi ……….. 7

2.1.4

Gambaran Klinik ……… 8

2.1.5

Patofisiologi ……… 8

2.2

Resistensi Insulin ………..

11

2.2.1

Mekanisme Resistensi Insulin pada PCOS ……… 13

viii   

2.2.3

Hiperinsulinemia dan Induksi Ovulasi ...

14

2.3

Metformin ……….

15

2.3.1

Metformin dan PCOS ……….

16

2.3.2

Ovulasi Spontan setelah Pengobatan dengan Metformin ………

16

2.3.3

Metformin dan Induksi Ovulasi dengan Clomiphene Citrate (CC) ……

17

2.4

Dosis dan Jangka Waktu Pemberian Metformin pada PCOS ………..

18

2.5

Efek Samping Metformin ……….………

19

2.6

Metformin XR (Extended Released) ………

19

BAB III METODE PENELITIAN

3.1

Desain Penelitian ……….

23

3.2

Tempat dan Waktu ………...

23

3.3

Populasi dan Sampel Penelitian ………

23

3.3.1

Populasi Penelitian ……….

23

3.3.2

Sampel Penelitian ………..

23

3.4

Kriteria Penelitian ………

23

3.4.1

Kriteria Inklusi ………...

24

3.4.2

Kriteria Ekslusi ………..

24

3.5

Variabel Penelitian ………..

24

3.5.1

Variabel Independen ………

24

3.5.2

Variabel Dependen ………..

24

3.6

Kerangka Konsep Penelitian ……….

25

3.7

Cara Kerja ……….

25

3.8

Batasan Operasional ……….

28

3.9

Pengolahan Data ………..

28

ix   

BAB IV HASIL DAN PEMBAHASAN

4.1

Sebaran Karakteristik ………..

29

4.2

Efek Samping ………..

30

4.3

Luaran ………..

32

BAB V KESIMPULAN DAN SARAN

5.1

Kesimpulan ………..

34

5.2

Saran ………

34

x   

DAFTAR GAMBAR

Gambar 1. Pengukuran diameter tiga dimensi dari ovarium untuk menghitung volume

Gambar 2. Kunci utama dari produksi androgen yang berlebihan pada polycystic ovary

Gambar 3. Mekanisme dari produksi androgen yang berlebihan pada polycystic ovary

Gambar 4. Peranan hperinsulinemia dalam patogenesa anovulasi dan hperandrogenisme

Gambar 5. Potensial mekanisme dari resistensi insulin pada polycystic ovary syndrome

Gambar 6. Metformin Extended Release

Gambar 7. Rerata kadar plasma berbanding waktu pada pemberian metformin IR dan

metformin XR

xi   

DAFTAR TABEL

Tabel 1. Sebaran Karakteristik Subjek menurut Kelompok Penelitian

Tabel 2. Efek Samping Minggu Pertama

Tabel 3. Efek Samping Minggu Kedua

Tabel 4. Efek Samping setelah Minggu Kedua

Tabel 5. Luaran Ovulasi dan Kehamilan

xii   

Comparison of the Effectiveness and Side Effects of Metformin XR and

Metformin IR in the Management of Clomiphene Citrate Resistant

PCOS

Perbandingan Efektifitas dan Efek Samping Metformin XR dan Metformin IR dalam

Pengobatan PCOS yang Resisten terhadap Clomiphene Citrate

Hedy Tan, Binarwan Halim, Yostoto B Kaban

Deparment of Obstetrics and Gynecology Medical Faculty of North Sumatera

University / Haji Adam Malik Central General Hospital / Pirngadi District General

Hospital / Halim Fertility Centre Medan

Abstract

Objective :

To assess the effectiveness and side effects of metformin XR once daily and

metformin IR three times daily in the management of clomiphene citrate resistant

(CC-resistant) PCOS.

Method :

This is a prospective randomized controlled study conducted at Halim Fertility

Centre Medan. Fifty nine CC-resistant PCOS women who met the inclusion criterias

were randomly allotted into metformin XR and metformin IR groups. Twenty nine

women in the metformin XR group were given 500 mg metformin XR once a day and 30

women in the metformin IR group were given 500 mg metformin IR once a day for the

first week, twice a day for the second week and three times a day after the second week.

All women in both group were given 10 days of 10 mg norethisterone for withdrawal

bleeding and 150 mg clomiphene citrate on day 2 to day 6 of withdrawal bleeding for

ovulation induction. TVS were carried out to determine the growth of follicles, ovulation

and pregnancy. All women were enquired regarding the side effects of treatment at the

end of the week.

Results :

The baseline characteristics were not significantly different between the two

xiii   

side effects of the treatment in the first week were also not significantly different between

the two groups with all the

p value

> 0.05. However there was significant difference

statistically between the two groups regarding side effects of the treatment in the second

and after the second week with the average

p value

< 0.05 which favoured the metformin

XR group. There were 2 patients dropped out from the study because of the side effects.

Each in the second and after the second week. Both of them were from metformin IR

group, however there weren’t statistically significant difference with the

p value

of 1.

The ovulation rate (65.5% vs 53.6%) and pregnancy rate (24.1% vs 17.9%) for

metformin XR group vs metformin IR group respectively. Even though there were higher

achievements in the ovulation and pregnancy rate for metformin XR group, there weren’t

significant differences after analyzed by statistic between the two groups with the

p value

of 0.358 and 0.561 respectively for ovulation and pregnancy rate.

Conclusion :

Metformin XR has better side effect profile and achieved higher ovulation

and pregnancy rate as compared to metformin IR in the management of CC-resistance

PCOS patients. More over metformin XR can be given once daily which can improve

patients compliance with the treatment.

Keywords :

Clomiphene citrate resistance PCOS, metformin XR, metformin IR

Abstrak

Tujuan : Untuk membandingkan efektifitas dan efek samping metformin XR sekali sehari

dan metformin IR 3 kali sehari dalam pengobatan PCOS yang resisten terhadap

clomiphene citrate.

Metode : Penelitian prospektif acak terkendali yang dilakukan di Halim Fertility Centre

Medan. Lima puluh sembilan wanita PCOS yang resisten terhadap clomiphene citrate

yang memenuhi kriteria inklusi di kelompokan secara acak ke dalam kelompok metformin

XR dan metformin IR. Dua puluh Sembilan wanita pada kelompok metformin XR

diberikan metformin XR 500 mg sekali sehari dan 30 wanita pada kelompok metformin

IR diberikan metformin IR 500 mg sekali sehari pada minggu pertama, dua kali sehari

xiv   

pada minggu ke dua dan tiga kali sehari setelah minggu ke dua. Semua wanita pada

kedua kelompok diberikan norethisterone 10 mg selama 10 hari untuk withdrawal

bleeding dan clomiphene citrate 150 mg pada hari ke dua sampai hari ke enam

withdrawal bleeding untuk induksi ovulasi. TVS dilakukan untuk memantau pertumbuhan

folikel, ovulasi dan kehamilan. Semua wanita tersebut di tanyakan tentang efek samping

pengobatan pada akhir minggu pengobatan.

Hasil : Tidak dijumpai perbedaan yang bermakna dalam karakteristik dasar antara

kedua kelompok dengan nilai p = 0,999 untuk umur dan 0,554 untuk BMI. Secara

statistik, tidak dijumpai perbedaan bermakna dalam efek samping pengobatan pada

minggu pertama antara kedua kelompok dengan semua nilai p > 0,05. Akan tetapi

dijumpai perbedaan yang bermakna secara statistik antara kedua kelompok dalam efek

samping pengobatan pada minggu kedua dan setelah minggu kedua dengan rerata nilai p

< 0,05 yang lebih baik pada kelompok metformin XR. Terdapat 2 wanita yang drop out

dari penelitian ini yang disebabkan oleh efek samping pengobatan. Satu wanita pada

minggu kedua dan 1 wanita setelah minggu kedua. Keduanya berasal dari kelompok

metformin IR, akan tetapi secara statistik tidak dijumpai perbedaan bermakna dengan

nilai p = 1. Rerata ovulasi adalah 65,5% dan kehamilan adalah 24,1% untuk kelompok

metformin XR. Rerata ovulasi adalah 53,6% dan kehamilan adalah 17,9% untuk

kelompok metformin IR. Walaupun terdapat rerata ovulasi dan kehamilan yang lebih

tinggi pada kelompok metformin XR, setelah di analisa secara statistik tidak dijumpai

perbedaan yang bermakna dengan nilai p = 0,358 untuk ovulasi dan 0,561 untuk

kehamilan.

Kesimpulan : Metformin XR mempunyai efek samping yang lebih baik dan mencapai

rerata ovulasi dan kehamilan yang lebih tinggi dibandingkan metformin IR dalam

pengobatan wanita PCOS yang resisten terhadap clomiphene citrate. Lagi pula

metformin XR dapat diberikan hanya satu kali sehari sehingga dapat meningkatan

kepatuhan pasien dalam pengobatannya.

Kata kunci : PCOS yang resisten terhadap clomiphene citrate, metformin XR, metformin

xv   

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies

affecting 5%–10% of reproductive age women

1

. This syndrome consist of combination

between clinical, ultrasonographic and laboratory features such as oligo/amenorrhoea,

oligo/anovulation, hirsutism, hyperandrogenaemia, specific ovarian morphology,

hyperinsulinaemia and insulin resistance. An internationally accepted definition was been

adopted in 2003 by the European Society for Human Reproduction and Embryology and

the American Society for Reproductive Medicine, known as the ESHRE/ASRM

Rotterdam consensus

2

. It required the presence of two of the following three diagnostic

criteria: [1] oligoamenorrhea or anovulation; [2] clinical or biochemical evidence of

hyperandrogenism; and [3] the presence of polycystic ovarian morphology.

The exact aetiology of PCOS is unknown. However, insulin resistance with

compensatory hyperinsulinemia is a prominent feature of the syndrome and appears to

have a pathophysiologic role in the hyperandrogenism of the disorder, especially in those

with CC resistance. Both lean and obese women with PCOS show evidence of decreased

insulin sensitivity

3

, but insulin resistance, accompanied by compensatory

hyperinsulinemia, is most marked when there is an interaction between obesity and the

syndrome

4,5

. There is ample evidence that hyperinsulinemia results in increased ovarian

androgen biosynthesis in vivo and in vitro

5,6

and decreased sex hormone–binding

globulin (SHBG) synthesis from the liver

7,8

, leading to increased bioavailability of free

androgens. This excess in local ovarian androgen production augmented by

hyperinsulinemia causes premature follicular atresia and anovulation

9,10

. Although this

idea remains controversial, hyperinsulinemia may have a direct effect on the

hypothalamus and/or pituitary to increase serum luteinizing hormone (LH) concentrations

and therefore indirectly increase LH-dependent ovarian androgen biosynthesis

5,8

,

possibly resulting in abnormal LH and follicle-stimulating hormone (FSH) release and

subsequent oligoamenorrhea. Hyperinsulinemia may also directly affect folliculogenesis

and may arrest growth of antral follicles after they have reached a diameter between 5

xvi   

Given the importance of hyperinsulinemia in the development of hyperandrogenism and

disrupted folliculogenesis, it seems likely that medications that act as insulin-sensitizing

agents may be useful in restoration of normal endocrinologic and clinical parameters of

this condition. Therapeutic measures directed at lowering insulin secretion in women

with PCOS should theoretically ameliorate their hyperandrogenism and restore normal

follicular growth, thus facilitating ovulation

11

. The most extensively studied

insulin-sensitizing drug in the treatment of PCOS is metformin

12,13

. Metformin

(dimethylbiguanide) is an orally administered drug used to lower blood glucose

concentrations in patients with noninsulin- dependent diabetes mellitus (NIDDM)

14

. It is

antihyperglycemic in action and does not cause hypoglycemia. Metformin enhances

insulin sensitivity in both the liver, where it inhibits hepatic glucose production, and the

peripheral tissue, where it increases glucose uptake and utilization in muscle tissue. By

increasing insulin sensitivity, metformin reduces insulin resistance, insulin secretion, and

hyperinsulinemia. Hence, metformin seems to be a perfect drug to treat patients with

PCOS, including those with CC resistance

12,13

. It was reported that metformin treatment

for patients with PCOS improves a patient’s menstrual cycle and increases the sensitivity

for the ovulation induction drug reaction, especially in women with CC-resistant

PCOS

11,12,13

.

Even though the use of metformin in PCOS patients so popular, until recently there was

no consensus regarding the doses, when and how long the drug should been given. Many

studies has been done, however the regimens been use were very wide in variety. The

conventional metformin used in many studies was metformin IR, this tandard metformin

suffers from the limitations of having to be administered two or three times a day and

with the attendant risk of triggering gastrointestinal symptoms such as nausea, vomit,

bloated, epigastric pain and diarrhea. This event making dose optimization problematic

and reduced patients compliances. Some studies showed the dropout rate in the

metformin group was 30% owing to side effects

15

.

To overcome the side effects and improved patients compliances of metformin

treatments, the joint consensus statement from the American Diabetes Association

xvii   

(ADA) and the European Society for the study of Diabetes (EASD) give advice on how

to minimize poor compliance with standard metformin. In the 5 point plan for introducing

metformin, the ADA/EASD draw attention to the recently introduced extended release

metformin

16

. Many studies showed this extended release metformin had similar

efficacies, lower side effects as compared to standard immediate release metformin. It

also improved patients compliances due to the simple once daily dosing

17-20

.

This study aimed to assessed the effectiveness and side effects of metformin XR once

daily and metformin IR three times daily in the management of CC-resistant PCOS.

Method

This is a prospective randomized, controlled study conducted at Halim Fertility Centre

Medan. The study protocol was approved by Health Research Ethical Committee of

North Sumatera c/o Medical School, Universitas Sumatera Utara. A total of 59 women

with CC-resistant PCOS were recruited. The diagnosis of PCOS was based on

ESHRE/ASRM

criteria, which included at least two of three criteria of the following: [1]

chronic anovulation; [2] clinical or biochemical signs of hyperandrogenism; and [3]

polycystic ovary (PCO) morphology, shown on ultrasound scan, defined as the presence

of 12 or more follicles (with one ovary being sufficient for diagnosis) measuring 2 - 9

mm in diameter or increase in ovarian volume of more than 10 mL. Clomiphene

resistance was defined as failure of follicular development after CC treatment up to 150

mg daily for 5 days for two cycles. Informed consent was obtained and all baseline

evaluations were carried out before entry to study. The body mass index (BMI, weight in

kilograms/the square of the height in meters) was calculated. Women who were eligible

and consented were randomly allotted to the metformin XR group (A) or metformin IR

group (B). Randomizations were done by picking an envelope labeled AB or BA. If the

AB labeled envelope was picked out, the first woman was assigned to group A and the

second woman was assigned to group B. Vice versa was apply if the BA labeled envelope

was picked out. The investigators and patients were not blinded to the treatment.

xviii   

Women in group A were given 500 mg metformin XR once a day and women in the

group B were given 500 mg metformin IR once a day for the first week, twice a day for

the second week and three times a day after the second week. All women in both groups

were given 10 days of 10 mg norethisterone for withdrawal bleeding and 150 mg

clomiphene citrate on day 2 to day 6 of withdrawal bleeding for ovulation induction. At

the end of the week, all women will be enquired regarding the side effects of the

treatment. A transvaginal ultrasound (TVS) were carried out to determine the growth of

follicles on day 8, 12 and 16 of withdrawal bleeding. If there was follicle with diameter

≥

18 mm (dominant follicle), TVS was carried out daily to determined ovulation. Women

were asked to have sexual intercourse after 34-36 hours every 2 day for 5 consecutive

times. If there was no dominant follicle, the treatment was considered failed. Urinary

pregnancy test was carried out after a week of missing period, and TVS was carried out

to confirmed pregnancy. Pregnancy was defined as the presence of a gestational sac seen

on TVS. All the side effects will be recorded and if the women were unable to tolerate the

treatment, they will be discharged from the study.

Statistical analysis was performed using the Statistical Package for Social Sciences

(SPSS) software version 17.0 for Windows. Comparisons of baseline values, side effects,

ovulation rates and pregnancy rates in the two groups were made by using the chi-square

test and t-test. A

p

value of less than 0.05 was considered statistically significant.

Results

A total of 59 women with CC-resistant PCOS were randomized with 29 women in group

A and 30 women in group B. The baseline characteristics were not significantly different

between the two groups with

p

value

of 0.999 and 0.554 for the age and BMI

respectively (Table 1). We did not analyzed the baseline characteristic of parity as all the

women in our study were nulliparous.

xix   

Table 1. Baseline Characteristic

 

 

Group A

Group B

P

n = 29

n = 30

X ± SD

X ± SD

Age (years)

29.31 ± 3.24

28.50 ± 3.25

0.999

BMI (Kg/m

2

)

27.39 ± 2.28

27.52 ± 2.81

0.554

p = t-Test

Statistically, side effects of the treatment in the first week were also not significantly

different between the two groups with all the

p value

> 0.05. However there was

significant difference statistically between the two groups regarding side effects of the

treatment in the second and after the second week with the average

p value

< 0.05 which

favored group A. There were 2 patients dropped out from the study because of the side

effects. Each in the second and after the second week. Both of them were from group B,

however there weren’t statistically significant difference with the

p value

of 1 (Table 2).

Table 2. Side Effects of Treatment

Group

A

Group

B

P

n

(%)

n

(%)

First week :

Nausea

5 (17.2%)

7 (23.3%)

0.561

Vomit

4 (13.8%)

5 (16.7%)

1.000

Bloated

5 (17.2%)

6 (20.0%)

0.786

Epigastric pain

3 (10.3%)

3 (10.0%)

1.000

Diarrhea

3 (10.3%)

4 (13.3%)

1.000

Drop Out

0

0

-

Second week :

Nausea

3 (10.3%)

11 (36.7%)

0.018

xx   

Bloated

0

11 (36.7%)

0.000

Epigastric pain

1 (3.4%)

11 (36.7%)

0.002

Diarrhea

1 (3.4%)

7 (23.3%)

0.064

Drop Out

0

1 (3.3%)

1.000

After second week :

Nausea

2 (6.9%)

14 (48.3%)

0.000

Vomit

0

10 (34.5%)

0.001

Bloated

1 (3.4%)

14 (48.3%)

0.000

Epigastric pain

0

9 (31.0%)

0.004

Diarrhea 0

9

(31.0%)

0.004

Drop Out

0

1 (3.3%)

1.000

p = chi Square 

The ovulation rate (65.5% vs 53.6%) and pregnancy rate (24.1% vs 17.9%) for group A

vs group B respectively. Even though there were higher achievements in the ovulation

and pregnancy rate for group A, there weren’t significant differences after analyzed by

statistic between the two groups with the

p value

of 0.358 and 0.561 respectively for

ovulation and pregnancy rate (Table 3).

Table 3. Ovulation and Pregnancy Rate

Group A

Group B

P

n = 29

n = 28

n (%)

n (%)

Ovulation

19 (65.5%)

15 (53.6%)

0.358

Pregnancy

7 (24.1%)

5 (17.9%)

0.561

xxi   

Discussion

The beneficial effects of metformin in the management of PCOS are now well

established, particular in patients with CC-resistance. One of the limiting factors,

however, in the use of metformin has been its side effects, which have led to large

dropout rates in many studies. These side effects were well known not only in the PCOS

patients, many of NIDDM patients whose were on metformin treatment also suffered

from these side effects and led to reduction in the compliance with the treatment. To

overcome the side effects and improved patients compliances of metformin treatments,

the joint consensus statement from the American Diabetes Association (ADA) and the

European Society for the study of Diabetes (EASD) give advice on how to minimize poor

compliance with standard metformin. In the 5 point plan for introducing metformin, the

ADA/EASD draw attention to the recently introduced extended release metformin. Many

studies showed this extended release metformin had similar efficacies, lower side effects

as compared to standard immediate release metformin. It also improved patients

compliances due to the simple once daily dosing.

Our study showed that simple once daily dosing of 500 mg metformin XR achieved

higher ovulation and pregnancy rates as compared to 3 times daily of 500 mg metformin

IR (65.5% & 24.1% VS 53.6% & 17.9% respectively) even though after analyzed did

not showed any statistically significant with

p

value of 0.358 & 0.561 for ovulation and

pregnancy rate respectively. This findings are consistent with previous studies done by

Hwu et al

21

and Khorram et al

22

.

In contrast to ovulation and pregnancy rates, the side

effects of the treatment showed significantly differences between the two groups which

favored metformin XR group.

The primary outcome of our study is to see the effectiveness and side effects of low dose

simple once daily dosing metformin XR in the management of CC-resistance PCOS

patients as until recently there was no consensus regarding the used of this medication in

such patients. Our study showed it had the benefits as compared to standard dosing of

metformin IR.

xxii   

Even though this is a simple study, only based on the clinical outcomes without any

laboratories support to determine the effects of the treatment, hence it showed the

benefits. To further proved the beneficial of this simple metformin XR dosing, its

required more larger study with clinical and laboratories support to evaluate the effects of

this treatment.

Conclusion

Metformin XR has better side effect profile and achieved higher ovulation and pregnancy

rate as compared to metformin IR in the management of CC-resistance PCOS patients.

More over metformin XR can be given once daily which can improve patients

compliance with the treatment

References

1.

Murizah M Z, Ridzuan J, Adibah I et al. Comparison of clomiphene citrate,

metformin, or the combination of both for first-line ovulation induction,

achievement of pregnancy, and live birth in Asian women with polycystic ovary

syndrome: a randomized controlled trial. Fertility and Sterilit 2009;91(2):514-21.

2.

The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.

Revised 2003 consensus on diagnostic criteria and long-term health risks related

to polycystic ovary syndrome. Fertil Steril 2004;8:19-25.

3.

Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and

implications for pathogenesis. Endocr Rev 1997;18:774-800.

4.

Dunaif A, Segal K. R, Shelley D. R et al. Evidence for distinctive and intrinsic

defects in insulin action in polycystic ovary syndrome. Diabetes 1992;4:1257-66.

5.

Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin

action associated with an increased risk of non-insulin-dependent diabetes

mellitus. Am J Med 1995;98(1A):33-9.

6.

Homburg R. Polycystic ovary syndrome - from gynaecological curiosity to multi

system endocrinopathy. Hum Reprod 1996;1:29-39.

7.

Amato P & Simpson J. L. The genetics of polycystic ovary syndrome. Best Pract

xxiii   

8.

Poretsky L. On the paradox of induced hyperandrogenism in

insulin-resistant states. Endocrinol Rev 199;12:3-13.

9.

Webber L. J, Stubbs S, Stark J et al. Formation and early development of follicles

in the polycystic ovary. Lancet 2003;362:1017-21.

10.

Willis D. S, Watson H, Mason H. D et al. Premature response to luteinizing

hormone of granulosa cells from anolulatory women with polycystic ovary

syndrome: relevance to mechanisrn of anovulation. J Clin Endocrinol Metab

1998;83:3984-91.

11.

Velazquez E. M, Mendoza S. G, Hamer T et al. Metformin therapy in Polycystic

ovary syndrome reduces hyperinsulinemia, insulin resistance,

hyperandrogenaemia and systolic blood pressure while facilitating normal menses

and pregnancy. Metab Clin Exp 1994;43:647-54.

12.

Lord J. M, Flight I. H. K, Norman R. I. Metformin in polycystic ovary syndrome:

systematic review and meta-analysis. BMJ 2003;327 (7421):951-60.

13.

Kolodziejczyk B, Duleba A. J, Spaczynski R. Z et al. Metformin therapy

decreases hyperandrogenism and hyperinsulinemia in women with polycystic

ovary syndrome. Fertil Steril 2000;73 :1149-54.

14.

American Diabetes Association. In: Consensus Development Conference on

lnsulin Resistance; Diab. Care 1998;21:310-14.

15.

Thomas I. Siebert M, Thinus F et al. Is the addition of metformin efficacious in

the treatment of clomiphene citrate-resistant patients with polycystic ovary

syndrome? A structured literature review. Fertility and Sterility

2006;86(5):1432-37.

16.

Bailey CJ, Turner RC

.

American Diabetes Association

, "

Standards of Medical

Care in Diabetes Mellitus 2009”

,

Diabetes Care

,

2009

;

32(1)113-61.

17.

Timmins P, Donahue S, Meeker J et al. Steady-state Pharmacokinetics of a Novel

Extended-Release Metformin Formulation. Clin Pharmacokinet 2005;

44(7):721-9.

18.

Levy J, Cobas R.A, Gomes M.B. Assessment of efficacy and tolerability of once

daily extended release metformin in patients with type 2 diabetes mellitus.

Diabetology & Metabolic Syndrome 2010;2:16.

xxiv   

19.

Davidson J, Howlett H. New prolonged-release metformin improves

gastrointestinal tolerability. British Journal of Diabetes and Vascular Disease

2004;4(4):273-77.

20.

Jabbour S, Ziring B. Advantages of extended-release metformin in patients with

type 2 diabetes mellitus. Postgraduate Medicine 2011;123(1):15-23

21.

Hwu Y. M, Lin S. Y, Huang W. Y et al. Ultra-short metformin pretreatment for

clomiphene citrate-resistant polycystic ovary syndrome. Int J Gynaecol Obstet

2005;90:39-43.

22.

Khorram O, Jason P, Helliwell et al. Two weeks of metformin improves

clomiphene citrate-induced ovulation and metabolic profiles in women with

polycystic ovary syndrome. Fertil Steril 2006;85:1448-51.

xii   

Comparison of the Effectiveness and Side Effects of Metformin XR and

Metformin IR in the Management of Clomiphene Citrate Resistant

PCOS

Perbandingan Efektifitas dan Efek Samping Metformin XR dan Metformin IR dalam

Pengobatan PCOS yang Resisten terhadap Clomiphene Citrate

Hedy Tan, Binarwan Halim, Yostoto B Kaban

Deparment of Obstetrics and Gynecology Medical Faculty of North Sumatera

University / Haji Adam Malik Central General Hospital / Pirngadi District General

Hospital / Halim Fertility Centre Medan

Abstract

Objective :

To assess the effectiveness and side effects of metformin XR once daily and

metformin IR three times daily in the management of clomiphene citrate resistant

(CC-resistant) PCOS.

Method :

This is a prospective randomized controlled study conducted at Halim Fertility

Centre Medan. Fifty nine CC-resistant PCOS women who met the inclusion criterias

were randomly allotted into metformin XR and metformin IR groups. Twenty nine

women in the metformin XR group were given 500 mg metformin XR once a day and 30

women in the metformin IR group were given 500 mg metformin IR once a day for the

first week, twice a day for the second week and three times a day after the second week.

All women in both group were given 10 days of 10 mg norethisterone for withdrawal

bleeding and 150 mg clomiphene citrate on day 2 to day 6 of withdrawal bleeding for

ovulation induction. TVS were carried out to determine the growth of follicles, ovulation

and pregnancy. All women were enquired regarding the side effects of treatment at the

end of the week.

Results :

The baseline characteristics were not significantly different between the two

xiii   

side effects of the treatment in the first week were also not significantly different between

the two groups with all the

p value

> 0.05. However there was significant difference

statistically between the two groups regarding side effects of the treatment in the second

and after the second week with the average

p value

< 0.05 which favoured the metformin

XR group. There were 2 patients dropped out from the study because of the side effects.

Each in the second and after the second week. Both of them were from metformin IR

group, however there weren’t statistically significant difference with the

p value

of 1.

The ovulation rate (65.5% vs 53.6%) and pregnancy rate (24.1% vs 17.9%) for

metformin XR group vs metformin IR group respectively. Even though there were higher

achievements in the ovulation and pregnancy rate for metformin XR group, there weren’t

significant differences after analyzed by statistic between the two groups with the

p value

of 0.358 and 0.561 respectively for ovulation and pregnancy rate.

Conclusion :

Metformin XR has better side effect profile and achieved higher ovulation

and pregnancy rate as compared to metformin IR in the management of CC-resistance

PCOS patients. More over metformin XR can be given once daily which can improve

patients compliance with the treatment.

Keywords :

Clomiphene citrate resistance PCOS, metformin XR, metformin IR

Abstrak

Tujuan : Untuk membandingkan efektifitas dan efek samping metformin XR sekali sehari

dan metformin IR 3 kali sehari dalam pengobatan PCOS yang resisten terhadap

clomiphene citrate.

Metode : Penelitian prospektif acak terkendali yang dilakukan di Halim Fertility Centre

Medan. Lima puluh sembilan wanita PCOS yang resisten terhadap clomiphene citrate

yang memenuhi kriteria inklusi di kelompokan secara acak ke dalam kelompok metformin

XR dan metformin IR. Dua puluh Sembilan wanita pada kelompok metformin XR

diberikan metformin XR 500 mg sekali sehari dan 30 wanita pada kelompok metformin

IR diberikan metformin IR 500 mg sekali sehari pada minggu pertama, dua kali sehari

xiv   

pada minggu ke dua dan tiga kali sehari setelah minggu ke dua. Semua wanita pada

kedua kelompok diberikan norethisterone 10 mg selama 10 hari untuk withdrawal

bleeding dan clomiphene citrate 150 mg pada hari ke dua sampai hari ke enam

withdrawal bleeding untuk induksi ovulasi. TVS dilakukan untuk memantau pertumbuhan

folikel, ovulasi dan kehamilan. Semua wanita tersebut di tanyakan tentang efek samping

pengobatan pada akhir minggu pengobatan.

Hasil : Tidak dijumpai perbedaan yang bermakna dalam karakteristik dasar antara

kedua kelompok dengan nilai p = 0,999 untuk umur dan 0,554 untuk BMI. Secara

statistik, tidak dijumpai perbedaan bermakna dalam efek samping pengobatan pada

minggu pertama antara kedua kelompok dengan semua nilai p > 0,05. Akan tetapi

dijumpai perbedaan yang bermakna secara statistik antara kedua kelompok dalam efek

samping pengobatan pada minggu kedua dan setelah minggu kedua dengan rerata nilai p

< 0,05 yang lebih baik pada kelompok metformin XR. Terdapat 2 wanita yang drop out

dari penelitian ini yang disebabkan oleh efek samping pengobatan. Satu wanita pada

minggu kedua dan 1 wanita setelah minggu kedua. Keduanya berasal dari kelompok

metformin IR, akan tetapi secara statistik tidak dijumpai perbedaan bermakna dengan

nilai p = 1. Rerata ovulasi adalah 65,5% dan kehamilan adalah 24,1% untuk kelompok

metformin XR. Rerata ovulasi adalah 53,6% dan kehamilan adalah 17,9% untuk

kelompok metformin IR. Walaupun terdapat rerata ovulasi dan kehamilan yang lebih

tinggi pada kelompok metformin XR, setelah di analisa secara statistik tidak dijumpai

perbedaan yang bermakna dengan nilai p = 0,358 untuk ovulasi dan 0,561 untuk

kehamilan.

Kesimpulan : Metformin XR mempunyai efek samping yang lebih baik dan mencapai

rerata ovulasi dan kehamilan yang lebih tinggi dibandingkan metformin IR dalam

pengobatan wanita PCOS yang resisten terhadap clomiphene citrate. Lagi pula

metformin XR dapat diberikan hanya satu kali sehari sehingga dapat meningkatan

kepatuhan pasien dalam pengobatannya.

Kata kunci : PCOS yang resisten terhadap clomiphene citrate, metformin XR, metformin

xv   

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies

affecting 5%–10% of reproductive age women

1

. This syndrome consist of combination

between clinical, ultrasonographic and laboratory features such as oligo/amenorrhoea,

oligo/anovulation, hirsutism, hyperandrogenaemia, specific ovarian morphology,

hyperinsulinaemia and insulin resistance. An internationally accepted definition was been

adopted in 2003 by the European Society for Human Reproduction and Embryology and

the American Society for Reproductive Medicine, known as the ESHRE/ASRM

Rotterdam consensus

2

. It required the presence of two of the following three diagnostic

criteria: [1] oligoamenorrhea or anovulation; [2] clinical or biochemical evidence of

hyperandrogenism; and [3] the presence of polycystic ovarian morphology.

The exact aetiology of PCOS is unknown. However, insulin resistance with

compensatory hyperinsulinemia is a prominent feature of the syndrome and appears to

have a pathophysiologic role in the hyperandrogenism of the disorder, especially in those

with CC resistance. Both lean and obese women with PCOS show evidence of decreased

insulin sensitivity

3

, but insulin resistance, accompanied by compensatory

hyperinsulinemia, is most marked when there is an interaction between obesity and the

syndrome

4,5

. There is ample evidence that hyperinsulinemia results in increased ovarian

androgen biosynthesis in vivo and in vitro

5,6

and decreased sex hormone–binding

globulin (SHBG) synthesis from the liver

7,8

, leading to increased bioavailability of free

androgens. This excess in local ovarian androgen production augmented by

hyperinsulinemia causes premature follicular atresia and anovulation

9,10

. Although this

idea remains controversial, hyperinsulinemia may have a direct effect on the

hypothalamus and/or pituitary to increase serum luteinizing hormone (LH) concentrations

and therefore indirectly increase LH-dependent ovarian androgen biosynthesis

5,8

,

possibly resulting in abnormal LH and follicle-stimulating hormone (FSH) release and

subsequent oligoamenorrhea. Hyperinsulinemia may also directly affect folliculogenesis

and may arrest growth of antral follicles after they have reached a diameter between 5

xvi   

Given the importance of hyperinsulinemia in the development of hyperandrogenism and

disrupted folliculogenesis, it seems likely that medications that act as insulin-sensitizing

agents may be useful in restoration of normal endocrinologic and clinical parameters of

this condition. Therapeutic measures directed at lowering insulin secretion in women

with PCOS should theoretically ameliorate their hyperandrogenism and restore normal

follicular growth, thus facilitating ovulation

11

. The most extensively studied

insulin-sensitizing drug in the treatment of PCOS is metformin

12,13

. Metformin

(dimethylbiguanide) is an orally administered drug used to lower blood glucose

concentrations in patients with noninsulin- dependent diabetes mellitus (NIDDM)

14

. It is

antihyperglycemic in action and does not cause hypoglycemia. Metformin enhances

insulin sensitivity in both the liver, where it inhibits hepatic glucose production, and the

peripheral tissue, where it increases glucose uptake and utilization in muscle tissue. By

increasing insulin sensitivity, metformin reduces insulin resistance, insulin secretion, and

hyperinsulinemia. Hence, metformin seems to be a perfect drug to treat patients with

PCOS, including those with CC resistance

12,13

. It was reported that metformin treatment

for patients with PCOS improves a patient’s menstrual cycle and increases the sensitivity

for the ovulation induction drug reaction, especially in women with CC-resistant

PCOS

11,12,13

.

Even though the use of metformin in PCOS patients so popular, until recently there was

no consensus regarding the doses, when and how long the drug should been given. Many

studies has been done, however the regimens been use were very wide in variety. The

conventional metformin used in many studies was metformin IR, this tandard metformin

suffers from the limitations of having to be administered two or three times a day and

with the attendant risk of triggering gastrointestinal symptoms such as nausea, vomit,

bloated, epigastric pain and diarrhea. This event making dose optimization problematic

and reduced patients compliances. Some studies showed the dropout rate in the

metformin group was 30% owing to side effects

15

.

To overcome the side effects and improved patients compliances of metformin

treatments, the joint consensus statement from the American Diabetes Association

xvii   

(ADA) and the European Society for the study of Diabetes (EASD) give advice on how

to minimize poor compliance with standard metformin. In the 5 point plan for introducing

metformin, the ADA/EASD draw attention to the recently introduced extended release

metformin

16

. Many studies showed this extended release metformin had similar

efficacies, lower side effects as compared to standard immediate release metformin. It

also improved patients compliances due to the simple once daily dosing

17-20

.

This study aimed to assessed the effectiveness and side effects of metformin XR once

daily and metformin IR three times daily in the management of CC-resistant PCOS.

Method

This is a prospective randomized, controlled study conducted at Halim Fertility Centre

Medan. The study protocol was approved by Health Research Ethical Committee of

North Sumatera c/o Medical School, Universitas Sumatera Utara. A total of 59 women

with CC-resistant PCOS were recruited. The diagnosis of PCOS was based on

ESHRE/ASRM

criteria, which included at least two of three criteria of the following: [1]

chronic anovulation; [2] clinical or biochemical signs of hyperandrogenism; and [3]

polycystic ovary (PCO) morphology, shown on ultrasound scan, defined as the presence

of 12 or more follicles (with one ovary being sufficient for diagnosis) measuring 2 - 9

mm in diameter or increase in ovarian volume of more than 10 mL. Clomiphene

resistance was defined as failure of follicular development after CC treatment up to 150

mg daily for 5 days for two cycles. Informed consent was obtained and all baseline

evaluations were carried out before entry to study. The body mass index (BMI, weight in

kilograms/the square of the height in meters) was calculated. Women who were eligible

and consented were randomly allotted to the metformin XR group (A) or metformin IR

group (B). Randomizations were done by picking an envelope labeled AB or BA. If the

AB labeled envelope was picked out, the first woman was assigned to group A and the

second woman was assigned to group B. Vice versa was apply if the BA labeled envelope

was picked out. The investigators and patients were not blinded to the treatment.

xviii   

Women in group A were given 500 mg metformin XR once a day and women in the

group B were given 500 mg metformin IR once a day for the first week, twice a day for

the second week and three times a day after the second week. All women in both groups

were given 10 days of 10 mg norethisterone for withdrawal bleeding and 150 mg

clomiphene citrate on day 2 to day 6 of withdrawal bleeding for ovulation induction. At

the end of the week, all women will be enquired regarding the side effects of the

treatment. A transvaginal ultrasound (TVS) were carried out to determine the growth of

follicles on day 8, 12 and 16 of withdrawal bleeding. If there was follicle with diameter

≥

18 mm (dominant follicle), TVS was carried out daily to determined ovulation. Women

were asked to have sexual intercourse after 34-36 hours every 2 day for 5 consecutive

times. If there was no dominant follicle, the treatment was considered failed. Urinary

pregnancy test was carried out after a week of missing period, and TVS was carried out

to confirmed pregnancy. Pregnancy was defined as the presence of a gestational sac seen

on TVS. All the side effects will be recorded and if the women were unable to tolerate the

treatment, they will be discharged from the study.

Statistical analysis was performed using the Statistical Package for Social Sciences

(SPSS) software version 17.0 for Windows. Comparisons of baseline values, side effects,

ovulation rates and pregnancy rates in the two groups were made by using the chi-square

test and t-test. A

p

value of less than 0.05 was considered statistically significant.

Results

A total of 59 women with CC-resistant PCOS were randomized with 29 women in group

A and 30 women in group B. The baseline characteristics were not significantly different

between the two groups with

p

value

of 0.999 and 0.554 for the age and BMI

respectively (Table 1). We did not analyzed the baseline characteristic of parity as all the

women in our study were nulliparous.

xix   

Table 1. Baseline Characteristic

 

 

Group A

Group B

P

n = 29

n = 30

X ± SD

X ± SD

Age (years)

29.31 ± 3.24

28.50 ± 3.25

0.999

BMI (Kg/m

2

)

27.39 ± 2.28

27.52 ± 2.81

0.554

p = t-Test

Statistically, side effects of the treatment in the first week were also not significantly

different between the two groups with all the

p value

> 0.05. However there was

significant difference statistically between the two groups regarding side effects of the

treatment in the second and after the second week with the average

p value

< 0.05 which

favored group A. There were 2 patients dropped out from the study because of the side

effects. Each in the second and after the second week. Both of them were from group B,

however there weren’t statistically significant difference with the

p value

of 1 (Table 2).

Table 2. Side Effects of Treatment

Group

A

Group

B

P

n

(%)

n

(%)

First week :

Nausea

5 (17.2%)

7 (23.3%)

0.561

Vomit

4 (13.8%)

5 (16.7%)

1.000

Bloated

5 (17.2%)

6 (20.0%)

0.786

Epigastric pain

3 (10.3%)

3 (10.0%)

1.000

Diarrhea

3 (10.3%)

4 (13.3%)

1.000

Drop Out

0

0

-

Second week :

Nausea

3 (10.3%)

11 (36.7%)

0.018

xx   

Bloated

0

11 (36.7%)

0.000

Epigastric pain

1 (3.4%)

11 (36.7%)

0.002

Diarrhea

1 (3.4%)

7 (23.3%)

0.064

Drop Out

0

1 (3.3%)

1.000

After second week :

Nausea

2 (6.9%)

14 (48.3%)

0.000

Vomit

0

10 (34.5%)

0.001

Bloated

1 (3.4%)

14 (48.3%)

0.000

Epigastric pain

0

9 (31.0%)

0.004

Diarrhea 0

9

(31.0%)

0.004

Drop Out

0

1 (3.3%)

1.000

p = chi Square 

The ovulation rate (65.5% vs 53.6%) and pregnancy rate (24.1% vs 17.9%) for group A

vs group B respectively. Even though there were higher achievements in the ovulation

and pregnancy rate for group A, there weren’t significant differences after analyzed by

statistic between the two groups with the

p value

of 0.358 and 0.561 respectively for

ovulation and pregnancy rate (Table 3).

Table 3. Ovulation and Pregnancy Rate

Group A

Group B

P

n = 29

n = 28

n (%)

n (%)

Ovulation

19 (65.5%)

15 (53.6%)

0.358

Pregnancy

7 (24.1%)

5 (17.9%)

0.561

xxi   

Discussion

The beneficial effects of metformin in the management of PCOS are now well

established, particular in patients with CC-resistance. One of the limiting factors,

however, in the use of metformin has been its side effects, which have led to large

dropout rates in many studies. These side effects were well known not only in the PCOS

patients, many of NIDDM patients whose were on metformin treatment also suffered

from these side effects and led to reduction in the compliance with the treatment. To

overcome the side effects and improved patients compliances of metformin treatments,

the joint consensus statement from the American Diabetes Association (ADA) and the

European Society for the study of Diabetes (EASD) give advice on how to minimize poor

compliance with standard metformin. In the 5 point plan for introducing metformin, the

ADA/EASD draw attention to the recently introduced extended release metformin. Many

studies showed this extended release metformin had similar efficacies, lower side effects

as compared to standard immediate release metformin. It also improved patients

compliances due to the simple once daily dosing.

Our study showed that simple once daily dosing of 500 mg metformin XR achieved

higher ovulation and pregnancy rates as compared to 3 times daily of 500 mg metformin

IR (65.5% & 24.1% VS 53.6% & 17.9% respectively) even though after analyzed did

not showed any statistically significant with

p

value of 0.358 & 0.561 for ovulation and

pregnancy rate respectively. This findings are consistent with previous studies done by

Hwu et al

21

and Khorram et al

22

.

In contrast to ovulation and pregnancy rates, the side

effects of the treatment showed significantly differences between the two groups which

favored metformin XR group.

The primary outcome of our study is to see the effectiveness and side effects of low dose

simple once daily dosing metformin XR in the management of CC-resistance PCOS

patients as until recently there was no consensus regarding the used of this medication in

such patients. Our study showed it had the benefits as compared to standard dosing of

metformin IR.

xxii   

Even though this is a simple study, only based on the clinical outcomes without any

laboratories support to determine the effects of the treatment, hence it showed the

benefits. To further proved the beneficial of this simple metformin XR dosing, its

required more larger study with clinical and laboratories support to evaluate the effects of

this treatment.

Conclusion

Metformin XR has better side effect profile and achieved higher ovulation and pregnancy

rate as compared to metformin IR in the management of CC-resistance PCOS patients.

More over metformin XR can be given once daily which can improve patients

compliance with the treatment

References

1.

Murizah M Z, Ridzuan J, Adibah I et al. Comparison of clomiphene citrate,

metformin, or the combination of both for first-line ovulation induction,

achievement of pregnancy, and live birth in Asian women with polycystic ovary

syndrome: a randomized controlled trial. Fertility and Sterilit 2009;91(2):514-21.

2.

The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.

Revised 2003 consensus on diagnostic criteria and long-term health risks related

to polycystic ovary syndrome. Fertil Steril 2004;8:19-25.

3.

Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and

implications for pathogenesis. Endocr Rev 1997;18:774-800.

4.

Dunaif A, Segal K. R, Shelley D. R et al. Evidence for distinctive and intrinsic

defects in insulin action in polycystic ovary syndrome. Diabetes 1992;4:1257-66.

5.

Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin

action associated with an increased risk of non-insulin-dependent diabetes

mellitus. Am J Med 1995;98(1A):33-9.

6.

Homburg R. Polycystic ovary syndrome - from gynaecological curiosity to multi

system endocrinopathy. Hum Reprod 1996;1:29-39.

7.

Amato P & Simpson J. L. The genetics of polycystic ovary syndrome. Best Pract

LEMBARAN PENJELASAN KEPADA CALON SUBJEK PENELITIAN

Ibu-ibu Yth,

Nama saya dr. Hedy Tan, saat ini saya sedang menjalani program adaptasi Dokter

Spesialis di Departemen Obstetri dan Ginekologi Fakultas Kedokteran Universitas

Sumatera Utara.

Saya sedang meneliti tentang pemakaian obat insulin sensitizer (Metformin XR dan

Metformi IR) pada pasien dengan Polycystic Ovary Syndrome(PCOS) yang sudah

resisten terhadap Clomiphene Citrate (CC). Banyak penemuan yang mengatakan

bahwa pasien dengan PCOS juga mempunyai resistensi terhadap insulin, sehingga

pemberian obat untuk induksi ovulasi seperti CC tidak bekerja dengan baik. Dengan

diberikan obat insulin sensitizer seperti Metformin, hal ini akan membantu untuk

menurunkan resistensi insulin sehingga pemberian obat induksi ovulasi dapat bekerja

dengan baik, sehingga saya tertarik untuk meneliti hal tersebut.

Adapun tujuan penelitian ini adalah untuk mengetahui efektifitas dan efek samping

pemakaian Metformin XR dan Metformin IR pada pasien PCOS yang sudah resisten

terhadap CC.

Adapun manfaat penelitian ini bagi ibu-ibu, diharapkan bila terbukti bahwa efektifitas

Metformin XR sebanding atau lebih baik dari Metformin IR dan juga efek samping nya

lebih baik, maka hal ini dapat dipergunakan untuk membantu induksi ovulasi dan ibu-ibu

akan mendapatkan siklus haid yang teratur dann juga kemungkinan untuk hamil.

Pada penelitian ini, saya akan menanyakan tentang riwayat ibu, melakukan

pemeriksaan fisik, transvaginal scan dan juga pemberian obat-obatan, ibu-ibu akan

dipantau setiap minggu untuk melihat kemajuan pengobatan dan juga memantau efek

samping dari pengobatan.

Penelitian ini tidak berbahaya, apabila terjadi efek samping terkait dengan penelitian ini

akan ditangai oleh peneliti. Biaya penelitiann ini sepenuhnya tidak dibebankan kepada

ibu-ibu. Partisipasi ibu-ibu dalam penelitian ini bersifat sukarela dan tanpa paksaan

maupun tekanan dari pihak manapun. Seandainya ibu-ibu menolak untuk berpartisipasi

dalam penelitian ini, maka ibu tidak akan kehilangan hak sebagai pasien.

Setelah memahami berbagai hal yang menyangkut penelitian ini, diharapkan ibu-ibu

yang terpilih sebagai sukarela dapat mengisi lembaran persetujuan turut serta dalam

penelitian ini yang telah dipersiapkan.

Terima kasih saya ucapkan kepada ibu-ibu yang telah berpatisipasi di dalam penelitian

ini. Juka selama menjalani penelitian ini terdapat hal-hal yang kurang jelas maka ibu-ibu

dapat menghubungi saya, dr. Hedy Tan, Departemen Obstetri dan Ginekologi FK USU,

Telp : 061-76762111 atau telepon genggam 081397808000. Terima kasih.

Medan,

201…

Hormat saya,

LEMBARAN PERSETUJUAN PESERTA PENELITIAN

Yang bertanda tangan dibawah ini :

Nama

:……….

Umur

:……… tahun

Alamat :………

Dengan ini menyatakan :

Setelah mendapat penjelasan sepenuhnya dan menyadari serta memahami tentang

maksud dan tujuan serta tata laksana penelitian yang berjudul :

Perbandingan Efektifitas dan Efek Samping Pemakaian Metformin XR dan

Metformin IR dalam Pengobatan PCOS yang Resisten terhadap Clomiphene

Citrate

Saya menyatakan bersedia / tidak keberatan untuk dilibatkan dan berpartisipasi dalam

penelitian ini, dengan sewaktu – waktu dapat mengundurkan diri karena berbagai

alasan.

Demikian surat persetujuan ini saya buat dengan penuh kesadaran dan penuh

tanggung jawab tanpa paksaan dari pihak manapun.

Medan, 201…

Peneliti,

Yang

Membuat

Pernyataan,

Koleksi Data

Nomor

:……….. Kelompok

: A / B

Nama

:……….

Umur

:………..tahun

Paritas :……….

Berat

Badan

:………..kg

Tinggi Badan

:……….cm

BMI

:……….kg/m

2

Efek Samping

:

Efek Samping

Minggu 1

Minggu 2

¾

Minggu 2

Mual

Muntah

Kembung

Nyeri Ulu Hati

Diare

Drop

Out

TVS

:

TVS Hasil

Folikel (hari ke 8)

mm

Folikel (hari ke 12)

mm

Folikel (hari ke 16)

mm

Ovulasi

Ovulasi / tidak ovulasi

Perbandingan Efektifitas dan Efek Samping Pemakaian Metformin XR dan Metformin IR dalam Pengobatan PCOS yang Resisten terhadap Clomiphen Citrate 

No. Urut Nama Umur (thn) Paritas BMI (Kg/m2) Kelompok Efek Samping Minggu ke I Efek Samping Minggu ke II Efek Samping setelah Minggu ke II Outcome Mual Muntah Kembung Nyeri Ulu Hati Diare Drop Out Mual Muntah Kembung Nyeri Ulu Hati  Diare Drop Out Mual  Muntah Kembung Nyeri Ulu Hati Diare Drop Out Ovulasi Hamil

1 Ria Theresia 25 0 26.82 A tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 2 Indri 29 0 33.33 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 3 Friska 35 0 30.43 A tdk ada tdk ada ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 4 Verawati 26 0 32.91 B ada ada tdk ada tdk ada ada tdk ada tdk ada tdk ada ada tdk ada ada tdk ada tdk ada tdk ada ada tdk ada ada tdk ada Ovulasi tdk hamil 5 Rivana 29 0 28.65 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada tdk ada ada ada tdk ada tdk ada ada tdk ada tdk ovulasi tdk hamil 6 Dewi 36 0 25.79 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 7 Bertha 26 0 27.74 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada ada tdk ada tdk ada tdk ada ada tdk ada ada ada ada tdk ada Ovulasi Hamil 8 Anita 29 0 28.71 A ada tdk ada ada tdk ada ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 9 Rahma Syari 31 0 27.96 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil

10 Sondang 26 0 30.75 B ada ada ada tdk ada ada tdk ada ada ada ada ada ada ada

11 Monalisa 34 0 23.91 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 12 Rika Andriani 30 0 28.19 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada ada tdk ada ada ada tdk ada tdk ada tdk ovulasi tdk hamil 13 Elizabeth Pardede 27 0 28.96 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 14 Nova Juliana 26 0 22.19 A ada ada tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 15 Mirda 33 0 27.79 B ada ada ada ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada Ovulasi tdk hamil 16 Kartini Dewi 26 0 24.99 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 17 Nurlela Sari 35 0 20.31 B ada ada ada tdk ada tdk ada tdk ada ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada tdk ada tdk ada Ovulasi Hamil 18 Nila Puspita 27 0 26.83 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 19 Nurintan 32 0 30.06 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 20 Wenny  29 0 26.49 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 21 Tina 26 0 28.18 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 22 Nurul 25 0 28.22 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 23 Hermy Ekanita 30 0 31.85 A ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 24 Irayanti 32 0 26.64 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 25 Rosmawaty 27 0 26.16 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 26 Despita 24 0 28.44 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada ada tdk ada ada tdk ada Ovulasi tdk hamil 27 Dewi Lestari 35 0 27.71 B tdk ada tdk ada ada ada ada tdk ada ada tdk ada ada ada ada tdk ada ada ada ada ada tdk ada tdk ada Ovulasi tdk hamil 28 Sri Nani 30 0 27.41 A ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 29 Melawaty 35 0 27.73 A tdk ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 30 Brenda 26 0 24.27 B ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 31 Octanova 26 0 27.86 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 32 Sicilia 27 0 28.27 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada ada tdk ada tdk ada tdk ada ada tdk ada ada tdk ada ada tdk ada Ovulasi tdk hamil 33 Frisca Farida 34 0 30.26 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 34 Dina Putri 24 0 27.09 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada tdk ovulasi tdk hamil 35 Indrawati 29 0 27.58 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ovulasi tdk hamil 36 Mona 30 0 26.95 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 37 Cathrine 34 0 28.92 B tdk ada tdk ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada ada ada ada ada tdk ada tdk ada tdk ovulasi tdk hamil 38 Karningsih 25 0 23.31 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 39 Sintyche 30 0 26.01 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 40 Gisella 33 0 30.26 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 41 Christina 24 0 21.36 B ada tdk ada ada tdk ada tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada ada tdk ada ada tdk ada ada tdk ada tdk ovulasi tdk hamil 42 Rosmawani 27 0 26.49 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 43 Febrina 26 0 23.82 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada ada ada tdk ada tdk ada tdk ovulasi tdk hamil 44 Keumalah  27 0 23.13 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 45 Novita 27 0 24.89 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 46 Juliana 26 0 29.09 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi Hamil 47 Widiawati 31 0 28.51 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada tdk ada tdk ada ada tdk ada tdk ovulasi tdk hamil 48 Sriyanti 30 0 29.11 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 49 Windawati 27 0 28.06 A ada ada ada ada tdk ada tdk ada ada tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 50 Juliawaty 27 0 27.35 B tdk ada tdk ada ada tdk ada tdk ada tdk ada tdk ada tdk ada ada ada ada tdk ada ada ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 51 Cyntia 28 0 29.26 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 52 Melawaty 31 0 29.94 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 53 Susana 26 0 26.62 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 54 Andriana 29 0 27.53 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 55 Bernita 28 0 25.3 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada Ovulasi tdk hamil 56 Ernita 32 0 27.7 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 57 Husna 27 0 29.21 B ada ada tdk ada tdk ada tdk ada tdk ada ada ada ada ada tdk ada tdk ada ada ada ada ada ada ada

58 Julita 30 0 28.07 A tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil 59 Lindawati 29 0 26.22 B tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ada tdk ovulasi tdk hamil