Disertasi

Varian Gen LH Subunit Beta dan Indeks Testosteron sebagai Prediktor untuk Respons Ovarium Pasien Sindrom Ovarium Polikistik pada Program Fertilitas in Vitro. = Beta Subunit LH Gene Variant and Free Testosterone Index as Predictor for Ovarian Response of PolycysticOvariann Syndrome Patients in In Vitro Fertility Program.

Pada program fertilitas in vitro (FIV) dilakukan stimulasi ovarium pada pasien SOPK untuk mendapatkan sel telur yang cukup baik secara kuantitas dan kualitas. Namun, terdapat pasien SOPK hiporespons setelah diberikan stimulasi ovarium. Penelitian ini dilakukan untuk menganalisis faktor yang berperan sebagai prediktor respons yang tidak biasa tersebut. Penelitian ini menggunakan desain nested casecontrol dengan subjek pasien SOPK dan perbandingan kasus : kontrol adalah 1 : 2 dengan total sampel 122. Pengambilan data dilakukan pada bulan Mei 2021 hingga November 2022 di Morula IVF Jakarta. Sampel darah diambil pada hari ke-2 atau ke-3 menstruasi dan sampel cairan granulosa diambil saat tindakan ovum pick up (OPU). Sampel darah diperiksa kadar testosteron, SHBG, dan hormon basal FSH, AMH, E2, LH serta uji sekuensing varian gen LH subunit beta titik rs1800447 dan rs34349826. Sel granulosa dianalisis dengan qPCR untuk pemeriksaan ekspresi GDF-9 dan BMP-15. Hasilnya menunjukkan subjek memiliki kadar testosteron, SHBG dan indeks testosteron bebas normal (SOPK euandrogenik). Ditemukan varian gen LH subunit beta di kedua titik yaitu varian AT yang belum pernah dilaporkan di NCBI. Kadar testosteron, SHBG, dan indeks testosteron bebas serta varian genetik tidak berhubungan dengan respons stimulasi ovarium (nilai p > 0,05). Pada analisis multivariat dengan regresi logistik didapatkan kadar AMH dan FSH yang menjadi faktor prediksi kejadian hiporespons. Namun, berdasarkan analisis ROC, hanya FSH yang baik untuk digunakan sebagai prediksi hiporespons (AUC: 0,684) dengan cut-off < 7,02. Ekspresi GDF-9 dan BMP-15 ditemukan tidak berbeda bermakna antar kelompok polimorfisme dan juga antar kelompok respon (nilai p > 0,05). Disimpulkan bahwa pada pasien SOPK euandrogenik, kadar FSH merupakan prediktor yang cukup baik untuk memprediksi respon stimulasi ovarium dibandingkan polimorfisme pada LH subunit beta dan indeks testosteron bebas. Polimorfise juga ditemukan tidak mempengaruhi kualitas sel telur pada setiap kelompok respon stimulasi ovarium.
Kata kunci: fertilitas in-vitro, indeks testosteron bebas, varian gen LH subunit beta.


Polycystic ovary syndrome (PCOS) is a hormonal disorder commonly found in women who take part in the in vitro fertilization (IVF) program. The purpose of ovarian stimulation in IVF programme is to get sufficient eggs both in quantity and quality. PCOS patients generally give hyperresponsive to ovarian stimulation. However in practice, hyporesponsive is also found in PCOS patients. This study was conducted with the aim of analyzing factors that have the potential to be predictors of such unusual responses.This is a nested case-control study where the subjects consisted of women with PCOS. The case and control comparisons used were 1 : 2 with a total sample of 122. Blood samples were taken on the 2nd or 3rd day of menstruation, and granulosa cell from follicular fluid were collected during the ovum pick up (OPU) procedures. The levels of testosterone, SHBG, as well as basal hormones FSH, AMH, E2, and LH were measured from serum. Sequencing was conducted to determine the LH gene variants of subunits beta rs1 800447 and rs34349826. Granulosa cells were analyzed with qPCR for examination of GDF-9 and BMP-15 expression. The results showed that the subjects in this study had normal levels of testosterone, SHBG, and free testosterone index similar to healthy women in general, known as euandrogenic PCOS women. A LH subunit beta gene variant was found at both rs1800447 and rs34349826, where this variant had never been previously reported in NCBI, named the AT variant. Testosterone levels, SHBG, free testosterone index as well as genetic variants were not significantly different with the ovarian stimulation response (p-value > 0.05). In multivariate analysis with logistic regression, AMH and FSH levels were found to be the predictive factors of ovarian stimulation response in euandrogenic PCOS. Based on the ROC analysis, only FSH has predictive value in ovarian stimulation (AUC: 0.684). The cut-off of FSH value is < 7.02. The results of the GDF-9 and BMP-15 analysis showed no significant different with the varian of LH subunit beta groups and ovarian stimulation response (p-value > 0.05). This study concluded that the basal FSH levels can be used as predictors of the ovarian stimulation response in euandrogenic PCOS women, instead of LH subunit beta variance and free testosterone index. LH subunit beta variants did not affect the oocyte quality in both ovarian stimulation response groups.
Keywords: beta subunit LH gene variant, free testosterone index, in-vitro fertility.