Background: Women with diminished ovarian reserve (DOR) respond differently to gonadotropin medications.

Objective: This study investigates the relationship between effective gene expression in the steroidogenesis pathway and gonadotropin responsiveness in DOR.

Materials and Methods: In this case-control study, cumulus cells were obtained from women with DOR after gonadotropin administration (n = 20) and normal ovarian reserve (n = 20). They were divided into the following groups, oocyte number < 3 and oocyte number > 3. After RNA extraction and cDNA synthesis, quantitative polymerase chain reaction was performed to assess the expression levels of cytochrome P450 aromatase (CYP19A1), protein kinase A (PKA), and glycogen synthase kinase 3 beta (GSK3B) genes.

Results: The women with DOR had statistically significant lower expression of CYP19A1 and PKA genes in their cumulus cells compared to control group (p = 0.04, and p < 0.001, respectively). There was also lower expression of the GSK3B gene in DOR compared to control group, but it was not significant. Although the expression of the CYP19A1, PKA, and GSK3B genes was lower in women with < 3 oocytes compared to women with more oocytes, this difference was not statistically significant.

Conclusion: In conclusion, DOR may be associated with lower expression of CYP19A1 and PKA genes. Also, considering the decrease in the expression of these genes in people with DOR, the expression of these genes can be used as a tool to predict the treatment.

Key words: Ovarian, Reserve, Steroidogenesis, CYP19A1, PKA, GSK3B, Gonadotropin.

[1] Yin J, Chang H-M, Li R, Leung PCK. Recent progress in the treatment of women with diminished ovarian reserve. Gynecol Obstet Clin Med 2021; 1: 186–189.

[2] Zhang Q-L, Lei Y-L, Deng Y, Ma R-L, Ding X-S, Xue W, et al. Treatment progress in diminished ovarian reserve: Western and Chinese medicine. Chin J Integr Med 2023; 29: 361–367.

[3] Zhang Y, Zhang Ch, Shu J, Guo J, Chang H-M, Leung PCK, et al. Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: A systematic review and network meta-analysis. Hum Reprod Update 2020; 26: 247–263.

[4] Ata B, Seyhan A, Seli E. Diminished ovarian reserve versus ovarian aging: Overlaps and differences. Curr Opin Obstet Gynecol 2019; 31: 139–147.

[5] Tal R, Seifer DB. Ovarian reserve testing: A user’s guide. Am J Obstet Gynecol 2017; 217: 129–140.

[6] Olsen KW, Castillo-Fernandez J, Chan AC, la Cour Freiesleben N, Zedeler A, Bungum M, et al. Identification of a unique epigenetic profile in women with diminished ovarian reserve. Fertil Steril 2021; 115: 732–741.

[7] Zhu Q, Li Y, Ma J, Ma H, Liang X. Potential factors result in diminished ovarian reserve: A comprehensive review. J Ovarian Res 2023; 16: 208.

[8] Lunenfeld B, Bilger W, Longobardi S, Alam V, D’Hooghe T, Sunkara SK. The development of gonadotropins for clinical use in the treatment of infertility. Front Endocrinol 2019; 10: 429.

[9] Fa S, Pogrmic-Majkic K, Samardzija D, Glisic B, Kaisarevic S, Kovacevic R, et al. Involvement of ERK1/2 signaling pathway in atrazine action on FSH-stimulated LHR and CYP19A1 expression in rat granulosa cells. Toxicol Appl Pharmacol 2013; 270: 1–8.

[10] Damdimopoulou P, Chiang C, Flaws J. Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis. Reprod Toxicol 2019; 87: 32–41.

[11] Xiao Ch, Wang J, Zhang Ch. Synthesis, regulatory factors, and signaling pathways of estrogen in the ovary. Reprod Sci 2023; 30: 350–360.

[12] Gifford JAH. The role of WNT signaling in adult ovarian folliculogenesis. Reproduction 2015; 150: R137-R148.

[13] Li L, Shi X, Shi Y, Wang Z. The signaling pathways involved in ovarian follicle development. Front Physiol 2021; 12: 730196.

[14] Candelaria JI, Rabaglino MB, Denicol AC. Ovarian preantral follicles are responsive to FSH as early as the primary stage of development. J Endocrinol 2020; 247: 153–168.

[15] Casarini L, Crépieux P. Molecular mechanisms of action of FSH. Front Endocrinol 2019; 10: 305.

[16] Cakiroglu Y, Yuceturk A, Karaosmanoglu O, Kopuk SY, Korun ZEU, Herlihy N, et al. Ovarian reserve parameters and IVF outcomes in 510 women with poor ovarian response (POR) treated with intraovarian injection of autologous platelet rich plasma (PRP). Aging 2022; 14: 2513–2523.

[17] Lee S-Y, Kang Y-J, Kwon J, Nishi Y, Yanase T, Lee K-A, et al. miR-4463 regulates aromatase expression and activity for 17??-estradiol synthesis in response to follicle-stimulating hormone. Clin Exp Reprod Med 2020; 47: 194.

[18] Praveen VP, Ladjouze A, Sauter K-S, Pulickal A, Katharopoulos E, Trippel M, et al. Novel CYP19A1 mutations extend the genotype-phenotype correlation and reveal the impact on ovarian function. J Endocr Soc 2020; 4: bvaa030.

[19] Panghiyangani R, Soeharso P, Suryandari DA, Wiweko B, Kurniati M, Pujianto DA. CYP19A1 gene expression in patients with polycystic ovarian syndrome. J Hum Reprod Sci 2020; 13: 100–103.

[20] Jirge PR. Poor ovarian reserve. J Hum Reprod Sci 2016; 9: 63–69.

[21] Abu-Musa A, Haahr T, Humaidan P. Novel physiology and definition of poor ovarian response; clinical recommendations. Int J Mol Sci 2020; 21: 2110.

[22] Wu Y-G, Barad DH, Kushnir VA, Wang Q, Zhang L, Darmon SK, et al. With low ovarian reserve, hghly individualized egg retrieval (HIER) improves IVF results by avoiding premature luteinization. J Ovarian Res 2018; 11: 23.

[23] Song D, Huang X-L, Hong L, Yu J-M, Zhang Z-F, Zhang H-Q, et al. Sequence variants in FSHR and CYP19A1 genes and the ovarian response to controlled ovarian stimulation. Fertil Steril 2019; 112: 749–757.

[24] Puri P, Little-Ihrig L, Chandran U, Law NC, Hunzicker-Dunn M, Zeleznik AJ. Protein kinase A: A master kinase of granulosa cell differentiation. Sci Rep 2016; 6: 28132.

[25] Wang W, Wu K, Jia M, Sun S, Kang L, Zhang Q, et al. Dynamic changes in the global microRNAome and transcriptome identify key nodes associated with ovarian development in chickens. Front Genet 2018; 9: 491.

[26] Wang Y, Cheng T, Lu M, Mu Y, Li B, Li X, et al. TMT-based quantitative proteomics revealed follicle-stimulating hormone (FSH)-related molecular characterizations for potentially prognostic assessment and personalized treatment of FSH-positive non-functional pituitary adenomas. EPMA J 2019; 10: 395–414.

[27] Zareifard A. Le rôle de Janus Kinase 3 ( JAK3) dans le développement folliculaire [M.Sc. thesis]. Montreal University; 2022.