Diagnostic Markers of Primary Infertility in Women of Reproductive Age with Hypothalamic Dysfunction in the Pubertal Period
¹Scientific Centre for Family Health and Human Reproduction Problems, Irkutsk, the Russian Federation; ²Amur State Medical Academy, Blagoveshchensk, the Russian Federation
*Corresponding author: Irina V. Zhukovets, PhD. Head of Department of Obstetrics and Gynecology, Amur State Medical Academy. Blagoveshchensk, the Russian Federation. E-mail: email@example.com
Published: September 16, 2017. doi: 10.21103/Article7(3)_OA10
The aim of the study was to assess fertility in women of reproductive age with hypothalamic dysfunction (HD) in the pubertal period and to determine the diagnostic significance of pro-inflammatory (TNF-α and IL-1β), anti-inflammatory cytokine (IL-10) and NF-kB activity in the diagnosis of primary infertility in these women.
Materials and Methods: Fertility was assessed in 86 women of reproductive age with HD in the pubertal period. A comparative characteristic of fertile women (Group 1, n=46) and primary infertility women (Group 2, n=21) with HD in the pubertal period was performed. FPG and FPI were determined after 8 to 12 hours of fasting. Serum IRI concentrations were measured using an ELISA kit. The levels of TNF-α, IL-1β and IL-10 were determined in the venous blood serum after a 12-hour fasting, as well as in UA on the 21st day of the menstrual cycle using ELISA kits. The activity of NF-kB was determined in UA on the 21st day of the menstrual cycle using an enzyme immunoassay kit.
Results: BMI in Group 1 was significantly lower than in Group 2: 22.63±2.68 kg/m2 versus 27.05±4.03kg/m2 (p=0.000). WC in women of Group 1 was 66.11±5.66cm versus 78.52±10.54cm in Group 2 (p = 0.000); WC >80cm was found in 2(4.4%) and 14(66.7%) women, respectively (p = 0.000). The average levels of FPG and FPI were significantly higher in Group 2. Serum levels of TNF-α and IL-1β in Group 2 were significantly higher than in Group 1. The serum level of anti-inflammatory cytokine IL-10 was significantly lower in Group 2; accordingly, the TNF-α/IL-10 ratio in Group 2 was 1.8 times higher than in Group 1. The IL-1β level in UA (P=0.000) and the TNF-α/IL-10 ratio (P=0.02) were significantly higher in women of Group 2 than Group 1, which indicated the pronounced inflammatory effects of TNF-α in the endometrium. Imbalance in the production of pro-inflammatory and anti-inflammatory factors indicated the activation of the Th-1 immune response with the formation of the inflammatory reactions at the systemic level and in the endometrium. In women of Group 2, the NF-kB level in UA was 1.4 times higher than in Group 1 (P=0.000).
Conclusion: every fourth woman of reproductive age with HD in the puberty period has primary infertility. The results obtained indicate the activation of the Th-1 immune response with the formation of the inflammatory reactions at the systemic level and in the endometrium. Diagnostically significant markers of primary infertility are the serum TNF-α level and the UA levels of IL-1β and NF-kB.
1. Leshchenko OYa. Reproductive potential of modern man (analitycal review). Pediatric and Adolescent Reproductive Health. 2013.(5):10-22.
2. Labygina AV, Kolesnikova LI, Suturina LV, Danusevich IN Hormonal metabolic and immunogenetic characteristics of women with hypothalamic syndrome, obesity and reproductive disorders. Collection of scientific papers, Sworld. 2013;(2): 70-78.
3. Uvarova EV, Khashchenko EP Hypothalamic dysfunction: etiopathogenesis and clinic (literature review). Pediatric and Adolescent Reproductive Health. 2010;(1):65-76.
4. Zhukavets IV, Leshchenko OYa, Atalyan AV. Somatic health and menstrual cycle in obese and overweight adolescent girls with hypothalamic dysfunction. Pediatric and Adolescent Reproductive Health. 2016;(4):50-58
5. Kovaleva YuV. The role of obesity in the development of menstrual and reproductive disorders. Ross Vest Akush Ginekol. 2014;(2):43-51.
6. Liu C, Elmquist JK. Tipping the scales early: probing the long-term effects of obesity. J Clin Invest. 2012;122(11):3840-2. doi: 10.1172/JCI66409
7. Kolesnikova LI1, Kolesnikov SI1, Darenskaya MA2, Grebenkina LA1, Nikitina OA1, Lazareva LM1, Suturina LV1, Danusevich IN1, Druzhinina EB1, Semendyaev AA1. Activity of LPO Processes in Women with Polycystic Ovarian Syndrome and Infertility. Bull Exp Biol Med. 2017 Jan;162(3):320-322. doi: 10.1007/s10517-017-3605-5.
8. West S, Lashen H, Bloigu A, Franks S, Puukka K, Ruokonen A, et al. Irregular menstruation and hyperandrogenaemia in adolescence are associated with polycystic ovary syndrome and infertility in later life: Northern Finland Birth Cohort 1986 study. Hum Reprod. 2014;29(10): 2339-51. doi: 10.1093/humrep/deu200.
9. Salikhova AF, Farkhutdinova LM. [Immunological features of obesity and their interrelation with violations of a carbohydrate and fatty exchanges]. Med Immunologiia. 2013;15(5): 465-470. [Article in Russian].
10. Stilidi EI. [The role of tumor necrosis factor alpha and interleukin-6 in the pathogenesis of NASH]. Krimskii Ter Zhurnal. 2012;18(1): 91-98.[Article in Russian].
11. Bohler HJ, Mokshagundam S, Winters SJ. Adipose tissue and reproduction in women. Fertil Steril. 2010;94(3):795-825. doi: 10.1016/j.fertnstert.2009.03.079.
12. Shpakov AO. [Functional state of the hypothalamic-pituitary-gonadal axis in diabetes mellitus]. Problemi Endocrinologii. 2010;56(5): 23-29.[Article in Russian].
13. Zastavna D, Sosnina K, Terpylyak O, Huleyuk N, Bezkorovayna H, Mikula M, Helner N. Cytogenetic and immunogenetic analysis of recurrent pregnancy loss in women. Tsitol Genet. 2014;48(4):44-50.
14. Pasquali R.The hypothalamic-pituitary-adrenal axis and sex hormones in chronic stress and obesity: pathophysiological and clinical aspects. Ann N Y Acad Sci. 2012;1264:20-35. doi: 10.1111/j.1749-6632.2012.06569.x.
15. Bellver J, Melo MA, Bosch E, Serra V, Remohi J, Pellicer A. Obesity and poor reproductive outcome: the potential role of the endometrium. Fertil Steril. 2007;88:446–51 .
16. Rich-Edwards JW, Goldman MB, Willet WC, Hunter DJ, Stamfer MJ, Colditz GA, et al. Adolescent body mass index and infertility caused by ovulation disorders. Am J Obstet Gynecol. 1994;171(1):171–7.
17. Zaadstra BM, Seidell JC, Van Noord PA, te Velde ER, Habbema JA, Vrieswijk B, Karbaat J. Fat and female fecundity: prospective study of effect of body fat distribution on conception rates. BMJ. 1993;306(6876):484–7.
18. Crosignani PG, Ragni G, Parazzini F, Wyssling H, Lombrosso G, Perotti L. Anthropometric indicators and response to gonadotrophin for ovulation induction. Hum Reprod. 1994;9(3):420–3.
19. Van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, et al. Obesity affects spontaneous pregnancy chances in subfertile ovulatory women. Hum Reprod. 2008;23(2):324–8
20. Hotamisligil GS1, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.Science. 1993 Jan 1;259(5091):87-91.
21. Hotamisligil GS1.Inflammatory pathways and insulin action.
Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S53-5.
22. Ruan H, Lodish HF.Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha.Cytokine Growth Factor Rev. 2003 Oct;14(5):447-55.
23. Ryden M, Dicker A, van Harmelen V, Hauner H, Brunnberg M, Perbeck L, et al. Mapping of early signaling events in tumor necrosis factor-alpha -mediated lipolysis in human fat cells. J Biol Chem. 2002 Jan 11;277(2):1085-91
24. Costa NT, Veiga Iriyoda TM, Kallaur AP, Delongui F, Alfieri DF, Lozovoy MA, et al. Influence of Insulin Resistance and TNF-α on the Inflammatory Process, Oxidative Stress, and Disease Activity in Patients with Rheumatoid Arthritis. Oxid Med Cell Longev. 2016;2016:8962763. doi: 10.1155/2016/8962763.
25. Zou C, Shao J. Role of adipocytokines in obesity- associated insulin resistance. J Nutr Biochem. 2008;19(5):277–86.
26. Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phsosphorylation of Ser(307). J Biol Chem. 2000;275(12):9047–54.
27. Groop LC, Saloranta C, Shank M, Bonadonna RC, Ferrannini E, DeFronzo RA. The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin- dependent diabetes mellitus. J Clin Endocrinol Metab. 1991;72(1):96–107.
28. Shevyakov SA, Zakharov IuM. [Studying of the role of tumor necrosis factor-alpha in regulation of erythropoiesis in erythroblastic islands cultures]. Ross Fiziol Zh Im I M Sechenova. 2013 Aug;99(8):993-1001. [Article in Russian]
29. Pavlov OV, Sel’kov SA. [In vitro production of IL-10 and IL-11 as a manifestation of "alternative activation" of placental macrophages]. Immunologiia. 2011;32(6):301-306 [Article in Russian].
30. Kaidashev IP.[Conception for permanent activation of nuclear factor kB as molecular basis for metabolic syndrom pathogenesis]. Patol Fiziol Eksp Ter. 2013 Jul-Sep;(3):65-72. [Article in Russian].
The fully formatted PDF version is available.
International Journal of Biomedicine. 2017;7(3):213-217. ©2017 International Medical Research and Development Corporation. All rights reserved.