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Abstrak :

Menopause menyebabkan hipoestrogenisme dan mengakibatkan penuaan kulit. Fitoestrogen dari biji T. foenum-graecum (klabet) diharapkan dapat mengatasi penuaan kulit pascamenopause. Penelitian ini bertujuan untuk mengetahui konsentrasi optimal ekstrak klabet dalam menstimulasi sekresi COL1A1 dan COL3A1, cara kerjanya melalui jalur reseptor estrogen α (REα) atau REβ, dan peran klabet dalam mengurangi kerutan serta meningkatkan ketebalan kulit wajah.

Studi in vitro menggunakan human dermal fibroblast (HDF) tua yang diperoleh dari kultur sel fibroblas kulit perempuan pascamenopause dan HDF muda dari prepusium, dilakukan di Laboratorium Universitas YARSI. Sekresi COL1A1 dan COL3A1 diperiksa dengan ELISA lalu ditambah antagonis REa dan b. Penelitian in vivo merupakan uji klinis acak tersamar ganda berdurasi 12 minggu, di RSCM, Januari–November 2019. Subjek 50 perempuan pascamenopause yang dibagi dua: kelompok perlakuan mendapat krim klabet 5% dan kelompok plasebo mendapat krim dasar. Skor kerutan dahi, crow’s feet, dan nasolabial diukur dengan skoring atlas skin aging Bazin dan tebal dermis dengan high resolution ultrasound (HRU) 18 MHz.

Ekstrak klabet 2 µg/mL merupakan konsentrasi optimal dalam meningkatkan sekresi COL1A1 dan COL3A1 pada HDF tua dan muda dibandingkan tanpa perlakuan dan 5 nM estradiol. Uji inhibisi menunjukkan hambatan REα 50%; REβ dan RE α,β sampai 75%. Penurunan skor kerutan dahi, crow’s feet, dan nasolabial berbeda bermakna pada kedua kelompok minggu ke-4, ke-8, dan ke-12.  Peningkatan selisih skor kerutan dahi, crow’s feet, dan nasolabial tidak bermakna pada kedua kelompok antara baseline, minggu ke-4, ke-8, dan ke-12. Ketebalan dermis meningkat bermakna pada minggu ke-4 dibandingkan baseline. Pada minggu ke-8 dibandingkan minggu ke-4 dan pada minggu ke-12 dibandingkan minggu ke-8, ketebalan dermis menurun bermakna pada kedua kelompok. Peningkatan selisih ketebalan dermis pada minggu ke-4 dan ke-8 tidak bermakna.

Simpulan: Ekstrak klabet 2 µg/mL meningkatkan COL1A1 dan COL3A1 lebih banyak dibandingkan kelompok tanpa perlakuan dan estradiol 5 nM. Klabet bekerja terutama melalui REβ. Penurunan skor kerutan kulit dan peningkatan ketebalan kulit wajah tidak bermakna dibandingkan plasebo. Diduga, krim klabet konsentrasi 5% tidak tepat untuk mengurangi kerutan dan menambah ketebalan kulit. Perlu penelitian lebih lanjut untuk mengetahui konsentrasi optimal klabet sebagai terapi penuaan kulit wajah pascamenopause.

 

Kata kunci: COL1A1, COL3A1, kerutan kulit, ketebalan dermis, klabet, pascamenopause, penuaan kulit wajah, Trigonella foenum-graecum.

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Hypoestrogenism in menopause leads to skin aging, for which phytoestrogen originated from the seeds of T. foenum-graecum (fenugreek) is expected to be a solution. This study aims to show the effect of phytoestrogen from fenugreek extract in stimulating COL1A1 and COL3A1 through its mechanism of action on estrogen receptor (ER) ERa or ERb and its role in diminishing facial wrinkles and increasing dermal thickness.

The in vitro study was carried out in YARSI University Laboratory throughout March 2017–March 2018. This study looks into the effect of fenugreek extract on collagen level secretion in old and young human dermal fibroblast (HDF) compared to control. The in vivo study was a randomized, double-blind, 12-week trial conducted in RSCM from January–November 2019. Fifty postmenopausal women divided into two groups: the intervention group was given 5% fenugreek cream while the placebo group was given base cream.

The in vitro study showed that a concentration of 2 mg/mL was the optimal dose to stimulate COL1A1 and COL3A1 secretion in both old and young HDF compared to control (no treatment) and 5 nM estradiol. The inhibition test demonstrated suppression of ERa by 50%; ERb and ERa,b by up to 75%, indicating that the fenugreek activates both receptors, especially ERb. However, the success of the in vitro study did not translate into the in vivo study. Both the intervention group and the placebo group were able to achieve statistically significant in facial wrinkle scores from all focus areas without any significant disparity between both groups at all timepoints. Dermal thickness of facial skin showed similar results for both groups with significant improvements in the 8^thweek compared to baseline and significant decrease by the 12^thweek.

Conclusion: Fenugreek extract with a concentration of 2 mg/mL increased COL1A1 and COL3A1 secretion more potently compared to control and estradiol 5 nM. However, the decrease in facial skin wrinkles scores and the increase in dermal thickness were not significant compared to placebo. We suspect that a concentration of 5% was not adequate for the expected antiaging effects. Further studies are necessary to determine a more appropriate fenugreek concentration to permit clinical use as a postmenopausal antiaging therapy.

 

Keywords: COL1A1, COL3A1, dermal thickness, fenugreek, postmenopausal women, facial skin aging, skin wrinkles, Trigonella foenum-graecum.

Abstrak :
Endometriosis sering dikaitkan dengan nyeri menstruasi dan nyeri pelvis. Penyakit ini terjadi sekitar 10-15% pada perempuan usia reproduksi . NGF, TRPA1 dan reseptor P2RX3 aktivitas gen terlibat dalam respon nyeri. Penelitian ini bertujuan untuk menganalisis tingkat ekspresi mRNA gen NGF, reseptor TRPA1 dan reseptor P2RX3 yang diduga disebabkan oleh perubahan tingkat metilasi DNA promoter gen tersebut, serta hubungannya pada intensitas nyeri subjek endometriosis.Sampel jaringan endometrium dan susukan endometriosis peritoneum diperoleh dari 20 subjek endometriosis, sementara jaringan endometrium kontrol diperoleh dari 20 subjek nir endometriosis. Metode yang digunakan untuk analisis metilasi DNA yaitu metode MSP dan perangkat lunak Image-J digunakan untuk menganalisis intensitas pita metilasi dari gen NGF, reseptor TRPA1 dan reseptor P2RX3R, selanjutnya digunakan metode qRT-PCR untuk analisis tingkat mRNA gen-gen tersebut. Penilaian intensitas nyeri dilakukan dengan menggunakan kuesioner standar skala penilaian numerik (NRS) melalui wawancara dengan pasien. Pada penelitian ini didapatkan hasil terdapat hubungan yang bermakna antara intensitas nyeri dan kejadian endometriosis (p>0,001). Hasil tersebut dibuktikan dengan terdapat perbedaan yang bermakna tingkat ekspresi relatif mRNA gen NGF, reseptor P2RX3 antara jaringan endometrium endometriosis dibandingkan dengan subjek nir endometriosis masing-masing nilai p= <0,05. Terdapat juga perbedaan yang bermakna tingkat metilasi DNA promotor gen NGF dan reseptor P2RX3 antara jaringan endometrium endometriosis dengan endometrium nir endometriosis (p<0,05). Selanjutnya, terdapat hubungan yang bermakna antara ekspesi mRNA NGF dan reseptor Reseptor P2RX3 dengan intensitas nyeri pada endometriosis (p<0,05), namun tidak terdapat hubungan antara tingkat metilasi DNA dengan ekspresi relatif mRNA gen NGF, reseptor reseptor TRPA1 pada endometriosis begitupun antara metilasi DNA dengan intensitas nyeri pada ketiga gen tersebut (p>0,05). Terjadi perubahan ekspresi relatif mRNA gen NGF, reseptor TRPA1 dan reseptor P2RX3 pada subjek endometriosis yang berhubungan dengan peningkatan intensitas nyeri pada endometriosis, namun mekanisme epigenetik metilasi DNA pada penelitian tersebut tidak berhubungan pada intensitas nyeri endometriosis. ...... Endometriosis is often associated with both cyclic menstrual pain and pelvic pain. It affects 10% of reproductive age women. NGF, TRPA1 and P2RX3 receptors gene activity are found to be involved in pain response. This study aims to analyze the methylation level of NGF gene, TRPA1 and P2RX3 receptors that might alter the mRNA expression in peritoneal endometriosis and endometrial tissue, as well as its correlation to the pain level in endometriosis patients.20 endometrial tissues and 20 peritoneal endometriosis tissues were obtained from patients, while 20 endometrium tissues as control were obtained from healthy women. First, each participant was given informed consent before the research begin. We used methylation specific PCR (MSP) and Image-J software to analyze the methylation level of NGF gene, TRPA1 and P2RX3 receptors; electrophoresis to analyze the band intensity; qRT-PCR to evaluate the mRNA level in each gene. Finally, we evaluated the pain level using the standardized questionnaire of numeric rating scale (NRS) by doing interviews with patients. In this study, it was found that there is a significant relationship between pain intensity and the incidence of endometriosis (p> 0.001). This results is proven by a significant difference in the mRNA expression level of NGF gene and P2RX3 receptor between endometrial endometriosis and endometrial non-endometriosis tissues, with each p value = <0.05. There is also a significant difference in the DNA methylation level of NGF gene and P2RX3 receptor between endometrial endometriosis and endometrial non-endometriosis tissues (p <0.05). There is a significant relationship between the mRNA expression level of NGF gene, P2RX3 receptor and pain intensity in endometrial endometriosis tissues (p <0.05). However, the results showed that there is no correlation between the DNA methylation level and the mRNA expression of NGF gene, TRPA1 and P2RX3 receptors. There is also no correlation between the DNA methylation level of NGF gene, TRPA1 and P2RX3 receptors and pain intensity in endometriosis tissue. There is an alteration of mRNA expression of NGF gene, TRPA1 and P2RX3 receptors which correlates to pain intensity in endometriosis patients. However, there is no correlation between DNA methylation level and pain intensity in endometriosis patients.

Abstrak :
Sindrom ovarium polikistik (SOPK) adalah kelainan endokrin yang paling banyak ditemukan dan memengaruhi 5–20% perempuan pada usia reproduksi. Kadar LH dan rasio LH dengan FSH lebih tinggi pada pasien SOPK nir-obese dibandingkan obese. Sekresi LH dan FSH dipengaruhi oleh pulsatilitas GnRH neuron GnRH di hipotalamus. Kisspeptin diduga sebagai regulator utama sekresi GnRH, sedangkan neurokinin B (NKB) dan dinorfin mengatur sekresi kisspeptin neuron KNDy. Namun, patofisiologi gangguan neuroendokrin pada pasien SOPK nir-obese belum dipahami sehingga diperlukan penelitian untuk mengetahui hubungan kadar kisspeptin, NKB dan dinorfin dengan rasio LH/FSH serta hubungannya dengan polimorfisme dan metilasi DNA gen KISS1. Penelitian ini menggunakan desain potong lintang di Klinik Yasmin, RSUPN dr. Cipto Mangunkusumo Kencana dan klaster Human Reproduction, Infertility and Family Planning IMERI UI pada bulan September 2021 sampai Januari 2023 dengan subjek penelitian 120 pasien SOPK nir-obese. Dilakukan pengukuran parameter komposisi tubuh, skor Ferriman-Gallwey dan pemeriksaan kadar FSH, LH, rasio LH/FSH, kisspeptin, NKB, dinorfin, leptin, adiponektin, AMH, glukosa darah puasa, insulin puasa, HOMA-IR, testosteron, dan SHBG. Dilakukan analisis polimorfisme rs4889 dan rs5780218 gen KISS1 danmetilasi DNA gen KISS1. Analisis bivariat dan analisis jalur dilakukan untuk mengetahui hubungan antarvariabel. Terdapat hubungan negatif antara dinorfin dengan kisspeptin, sedangkan kadar NKB tidak berhubungan dengan kisspeptin. Tidak ada hubungan kadar kisspeptin dengan rasio LH/FSH; namun, dinorfin berhubungan positif dengan rasio LH/FSH pada pada analisis bivariat maupun analisis jalur. Kadar AMH berhubungan dengan rasio LH/FSH baik pada kedua analisis. Pada analisis jalur, terdapat hubungan positif antara HOMA-IR dengan FAI dan antara FAI dengan AMH. Pada analisis polimorfisme gen KISS1tidak terdapat hubungan antara frekuensi genotipe maupun frekuensi alel rs4889 dan rs5780218 gen KISS1 SOPK nir-obese dengan kadar kisspeptin dan rasio LH/FSH. Tidak terdapat perbedaan bermakna antara metilasi DNA dengan kadar kisspeptin dan rasio LH/FSH. Terdapat hubungan antara peningkatan dinorfin dengan penurunan kadar kisspeptin. Hubungan dinorfin dengan rasio LH/FSH kemungkinan disebabkan oleh rendahnya kadar progesteron. Peningkatan AMH berhubungan dengan peningkatan rasio LH/FSH pada pasien SOPK nir-obese. AMH merupakan variabel perantara HOMA-IR dan FAI terhadap rasio LH/FSH. Tidak ada hubungan polimorfisme rs4889 dan rs5780218 gen KISS1 serta metilasi DNA gen KISS1 dengan kisspeptin dan rasio LH/FSH pada pasien SOPK nir-obese. Perlu penelitian lebih lanjut untuk mengetahui potensi terapi terhadap dinorfin dan AMH dalam tatalaksana pasien SOPK nir-obese. ......Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5–20% of reproductive age women. LH levels and LH/FSH ratios are higher in lean PCOS patients than in obese patients. LH and FSH secretion are influenced by GnRH pulsatility of GnRH neurons in the hypothalamus. Kisspeptin is thought to be the main regulator of GnRH secretion, whereas neurokinin B (NKB) and dynorphin regulate kisspeptin secretion in KNDy neurons. However, the pathophysiology of neuroendocrine disorders in lean PCOS patients is not well established. This study aims to determine the relationship between kisspeptin, NKB and dynorphin levels with the LH/FSH ratio and the relationship between polymorphism and DNA methylation of the KISS1 gene. This study used a cross-sectional design at the Yasmin Clinic, RSUPN dr. Cipto Mangunkusumo Kencana and the IMERI UI Human Reproduction, Infertility and Family Planning cluster from September 2021 to January 2023 with 120 lean PCOS patients as subjects. Body composition parameters, Ferriman-Gallwey score, FSH, LH, LH/FSH ratio, kisspeptin, NKB, dynorphin, leptin, adiponectin, AMH, fasting blood glucose, fasting insulin, HOMA-IR, testosterone, and SHBG were measured. Analysis of KISS1 gene polymorphisms of rs4889 and rs5780218 and DNA methylation were performed. Bivariate analysis and path analysis were performed to determine the relationship between variables. There was a negative relationship between dynorphin and kisspeptin, while NKB levels was not related to kisspeptin. There was no relationship between kisspeptin levels and the LH/FSH ratio; however, dynorphin was positively related to the LH/FSH ratio in both bivariate and pathway analysis. AMH levels was positively correlated with the LH/FSH ratio in both analyses. In path analysis, there is a positive relationship between HOMA-IR and FAI as well as between FAI and AMH. In the analysis of the KISS1 gene polymorphism, there was no significant difference between the genotype and allele frequencies of rs4889 and rs5780218 of the lean KISS1 gene with kisspeptin levels and the LH/FSH ratio. There was no significant difference between DNA methylation with kisspeptin levels and LH/FSH ratio. There is a relationship between the increased dynorphin and decreased kisspeptin levels. The association of dynorphins with the LH/FSH ratio may be due to low levels of progesterone. Increased AMH is associated with increased LH/FSH ratio in lean PCOS patients. AMH is an intermediary variable between HOMA-IR and FAI with the LH/FSH ratio. There is no relationship between the rs4889 and rs5780218 KISS1 gene polymorphisms and KISS1 gene DNA methylation with kisspeptin and the LH/FSH ratio in lean PCOS patients. Further research is required to determine the therapeutic potential of dynorphin and AMH in the management of lean PCOS patients.

Abstrak :
Latar Belakang: Fosforilasi tirosin, ekspresi akrosin dan reaksi akrosom memegang peran penting dalam proses pembuahan. Namun kriopreservasi menyebabkan perubahan fosforilasi tirosin, ekspresi akrosin dan reaksi akrosom yang akan mempengaruhi kualitas spermatozoa. Untuk itu diperlukan media krioprotektan yang ditambahkan dengan antioksidan untuk melindungi sperma dari efek kriopreservasi sehingga kualitas spermatozoa tetap terjaga. Tjuan: Penelitian ini menguji pengaruh suplementasi glutathione (GSH) pada media kriopreservasi terhadap fosforilasi tirosin, ekspresi akrosin dan reaksi akrosom pada proses pembuahan. Dalam penelitian ini, CPA modifikasi murni dibandingkan dengan CPA yang ditambah GSH dalam tiga konsentrasi berbeda. Bahan dan Cara: Sampel penelitian adalah jantan Deutchland Denken Yoken (DDY) strain Mus musculus albinus. Sperma tikus dikriopreservasi dan kemudian diukur beberapa parameter termasuk fosforilasi tirosin, ekspresi akrosin dan reaksi akrosom. Hasil: Kami menemukan bahwa menambahkan GSH ke CPA yang dimodifikasi meningkatkan fosforilasi tirosin, ekspresi akrosin, dan reaksi akrosom (menjaga integritas akrosom). Hasil penelitian menunjukkan bahwa kelompok yang ditambahkan GSH 1,00 mM mempunyai hasil paling tinggi diantara kelompok lainnya. Peningkatan yang signifikan ditemukan pada fosforilasi tirosin, ekspresi protein akrosin dan reaksi akrosom setelah penambahan 1,00 mM GSH. Kesimpulan: Suplementasi glutathione pada CPA termodifikasi dapat meningkatkan fosforilasi tirosin, ekspresi protein akrosin dan reaksi akrosom spermatozoa beku-cair. Secara umum pengobatan menggunakan GSH dengan dosis 1,00 mM dianggap paling efektif, dan modifikasi CPA dengan penambahan glutathione dapat meningkatkan fosforilasi tirosin, ekspresi akrosin dan reaksi akrosom pada spermatozoa kriopreservasi. ......Background: Tyrosine phosphorylation, acrosin, and acrosome reaction play an important role in fertilisation. However, cryopreservation causes changes in tyrosine phosphorylation, acrosin expression, and acrosome reaction which affect the quality of spermatozoa. Cryoprotectant media added with antioxidants is needed to protect spermatozoa from the effects of cryopreservation so that the quality of spermatozoa can be maintained. Objectives: This research examined the effect of glutathione (GSH) supplementation in Cryoprotectant Modification on tyrosine phosphorylation, acrosin expression, and acrosome reaction. In this research, pure modified Cryoprotectant (CPA) was compared with CPA supplemented with GSH in three different concentrations. Materials and Methods: The research sample was male mus musculus albinus strain Deutchland Denken Yoken (DDY). Mice spermatozoa was cryopreserved and several parameters were measured including tyrosine phosphorylation, acrosin expression, and acrosome reaction. Results: The addition of GSH to the modified CPA increased tyrosine phosphorylation, acrosin expression, and acrosome reaction (maintaining acrosome integrity). The group with 1.00 mM GSH obtained the highest results among the other groups. Significant increases were found in tyrosine phosphorylation, acrosin expression, and acrosome reaction after the addition of 1.00 mM GSH. Conclusion: Glutathione supplementation in modified CPA can increase tyrosine phosphorylation, acrosin expression, and acrosome reaction of frozen-thawed spermatozoa. Treatment using GSH at a dose of 1.00 mM is the most effective and modification of CPA with the addition of glutathione can improve the tyrosine phosphorylation, acrosin expression and acrosome reaction in cryopreserved spermatozoa.