Alterations in follicular fluid BMP-15 RNA expression in women undergoing controlled ovarian hyperstimulation

Background/aim: Bone morphogenetic protein-15 (BMP-15) is one of the maturation indicators of the ovarian follicular pool. The aim of this study was to investigate the possible difference of follicular fluid (FF) BMP-15 RNA expression among low, normal, and high responder women attending controlled ovarian hyperstimulation-intracytoplasmic sperm injection (COH-ICSI) cycles. Materials and methods: This cross-sectional study was conducted with 75 FFs of COH-ICSI cycles performed at the IVF Unit of University Hospital. Twenty FF from low response (group 1), 27 FF from normal response (group 2), and 28 FF from high response (group 3) were recruited for the study between September 2014 and February 2015. Cycle parameters were collected from patient files. FF BMP-15 RNA expression was evaluated with real-time polymerase chain reaction analysis. Statistical analysis was done with SPSS 16.0 version (SPSS Chicago, IL, USA). Results: The mean age, infertility duration, and body mass index (BMI) of patients were 31.1 ± 4.4 years, 7.4 ± 4.5 years, and 25.6 ± 4.1 kg/m2 , respectively. There was no significant difference among groups for age, infertility duration, and BMI. There was no significant difference among groups for fertilization rate, implantation rate, pregnancy rate, and live birth rate. Among the 3 groups, FF BMP-15 RNA overexpression and lower expression rates were not significantly different. In all groups, overexpression showed dominance. The pregnancy rate was 45% among women with lower expression and the pregnancy rate among women with overexpression was 26% (P = 0.02). BMP-15 overexpression showed impact on becoming pregnant (OR = 3.7, 95% CI = 1.245–11.299, P = 0.019). Conclusion: In this study, there was no significant difference in FF BMP-15 RNA expression levels among low, normal, and high responder women. However, overexpression of FF BMP-15 RNA showed a negative impact on pregnancy rates of women who attended COH-ICSI cycles.

PDF

___

1. Özkan ZS. Ovarian stimulation modalities in poor responders. Turkish Journal of Medical Sciences 2019 8; 49 (4): 959-962. doi: 10.3906/sag-1905-179
2. Persani L, Rossetti R, Di Pasquale E, Cacciatore C,Fabre S. The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders. Human Reproduction Update 2014; 20 (6): 869-883. doi: 10.1093/humupd/dmu036
3. Rossetti R, Ferrari I, Bestetti I, Moleri S, Brancati F et al. Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency. Human Mutation 2020; 41 (5): 983-997. doi: 10.1002/humu.23988
4. De Castro FC, Cruz MH, Leal CL. Role of growth differentiation factor 9 and bone morphogenetic protein 15 in ovarian function and their importance in mammalian female fertility - a review. Asian-Australasian Journal of Animal Sciences 2016; 29 (8): 1065-1074. doi: 10.5713/ajas.15.0797
5. Liu MN, Zhang K, Xu TM. The role of BMP15 and GDF9 in the pathogenesis of primary ovarian insufficiency. Human Fertility (Cambridge, England) 2019; 14: 1-8. doi: 10.1080/14647273.2019.1672107
6. Cerra C, Oliver J, Roberts SA, Horne G, Newman WG et al. A single nucleotide polymorphism of bone morphogenic protein-15 is not associated with ovarian reserve or response to ovarian stimulation. Human Reproduction 2014; 29 (12): 2832-2837. doi: 10.1093/humrep/deu264
7. Hanevik HI, Hilmarsen HT, Skjelbred CF, Tanbo T, Kahn JA. A single nucleotide polymorphism in BMP15 is associated with high response to ovarian stimulation. Reproductive Biomedicine Online 2011; 23 (1): 97-104. doi: 10.1016/j. rbmo.2011.02.015
8. Wu YT, Wang TT, Chen XJ, Zhu XM, Dong MY et al. Bone morphogenetic protein-15 in follicle fluid combined with age may differentiate between successful and unsuccessful poor ovarian responders. Reproductive Biology and Endocrinology 2012; 10: 116. doi: 10.1186/1477-7827-10-116
9. Cheraghi E, Soleimani Mehranjani M, Shariatzadeh SMA, Nasr Esfahani MH4, Alani B. N-acetylcysteine compared to metformin, improves the expression profile of growth differentiation factor-9 and receptor tyrosine kinase c-Kit in the oocytes of patients with polycystic ovarian syndrome. International Journal of Fertility and Sterility 2018; 11 (4): 270- 278. doi: 10.22074/ijfs.2018.5142
10. Moore RK, Shimasaki S. Molecular biology and physiological role of the oocyte factor, BMP-15. Molecular and Cellular Endocrinology 2005; 234 (1-2): 67-73.
11. Li Y, Li RQ, Ou SB, Zhang NF, Ren L et al. Increased GDF9 and BMP15 mRNA levels in cumulus granulosa cells correlate with oocyte maturation, fertilization, and embryo quality in humans. Reproductive Biology and Endocrinology 2014; 12: 81. doi: 10.1186/1477-7827-12-81
12. De Resende LOT, Vireque AA, Santana LF, Moreno DA, De Sá Rosa e Silva ACJ et al. Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation. Journal of Assisted Reproduction and Genetics 2012; 29 (10): 1057-1065. doi: 10.1007/s10815- 012-9825-8
13. Liu J, Wang B, Wei Z, Zhou P, Zu Y et al. Mutational analysis of human bone morphogenetic protein 15 in Chinese women with polycystic ovary syndrome. Metabolism: Clinical and Experimental 2011; 60 (11): 1511-1514. doi: 10.1016/j. metabol.2010.10.006
14. Voorhuis M, Broekmans FJ, Fauser BC, Onland-Moret NC, Van der Schouw YT. Genes involved in initial follicle recruitment may be associated with age at menopause. The Journal of Clinical Endocrinology and Metabolism 2011; 96 (3): E473-479. doi: 10.1210/jc.2010-1799
15. Wood JR, Dumesic DA, Abbott DH, Strauss JF 3rd. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. The Journal of Clinical Endocrinology and Metabolism 2007; 92 (2): 705-713. doi: 10.1210/jc.2006-2123
16. Wei LN, Liang XY, Fang C, Zhang MF. Abnormal expression of growth differentiation factor 9 and bone morphogenetic protein 15 in stimulated oocytes during maturation from women with polycystic ovary syndrome. Fertility and Sterility 2011; 96 (2): 464-468. doi: 10.1016/j.fertnstert.2011.05.036
17. Guéripel X, Brun V, Gougeon A. Oocyte bone morphogenetic protein 15, but not growth differentiation factor 9, is increased during gonadotropin-induced follicular development in the immature mouse and is associated with cumulus oophorus expansion. Biology of Reproduction 2006; 75 (6): 836-843. doi: 10.1095/biolreprod.106.055574
18. Pennetier S, Uzbekova S, Perreau C, Papillier P, Mermillod P, Dalbiès-Tran R. Spatio-temporal expression of the germ cell marker genes MATER, ZAR1, GDF9, BMP15, and VASA in adult bovine tissues, oocytes, and preimplantation embryos. Biology of Reproduction 2004; 71 (4): 1359-1366. doi: 10.1095/ biolreprod.104.030288
9. Machado MF, Caixeta ES, Sudiman J, Gilchrist RB, Thompson JG et al. Fibroblast growth factor 17 and bone morphogenetic protein 15 enhance cumulus expansion and improve quality of in vitro-produced embryos in cattle.Theriogenology 2015; 84 (3): 390-398. doi: 10.1016/j.theriogenology.2015.03.031
20. Inagaki K, Shimasaki S. Impaired production of BMP15 and GDF-9 mature proteins derived from proproteins WITH mutations in the proregion. Molecular and Cellular Endocrinology 2010; 328 (1-2): 1-7. doi: 10.1016/j. mce.2010.05.017
21. Gode F, Gulekli B, Dogan E, Korhan P, Dogan Set al. Influence of follicular fluid GDF9 and BMP15 on embryo quality. Fertility and Sterility 2011; 95 (7): 2274-2278. doi: 10.1016/j. fertnstert.2011.03.045
22. Wu YT, Lu XE, Wang TT, He RH, Xu J, Huang HF. Women with poor response to ovarian stimulation have increased follicular bone morphogenetic protein-15 levels. Zhejiang Da Xue Xue Bao Yi Xue Ban= Journal of Zhejiang University Medical Sciences 2007; 36 (5): 439-442 (in Chinese).