Hormonal regulation of serum and endometrial IL-1α, IL-1β and IL-1ra: IL-1 endometrial microenvironment of the human embryo at the apposition phase under physiological and supraphysiological steroid level conditions

Abstract

We have investigated serum and intracavitary levels of IL-1α, IL-1β and IL-1ra from agonadal women undergoing mock cycles ( n = 20) of oocyte donation as a clinical model of controlled hormonal stimulation. Further, we compared the intracavitary IL-1α, IL-1β and IL-1ra levels in the microenvironment of the human embryo at the apposition phase, day 5 after progesterone (P) administration using two different clinical models: oocyte donation ( n = 20) which provides physiological steroid levels and a higher implantation rate per embryo, and in vitro fertilization ( n = 6) with supraphysiological hormonal levels and a lower implantation rate. Serum (S) and uterine aspirates (U) were collected in patients treated with 2 mg per day of E 2-valerate (EV) (S1, U1), 6 mg per day of EV (S2, U2) and 6 mg per day EV plus 100 mg per day P (S3, U3), respectively. Serum IL-1α levels were negligible throughout the hormonal treatment, whereas intracavitary IL-1α concentration increased when P was added (U1= 0.008 ± 0.001 nmol/l; U2 = 0.009 ± 0.004 nmol/l; U3 = 0.053 ± 0.029 nmol/l, P > 0.05). Similarly, high and non-regulated serum IL-1β levels throughout the hormonal treatment were found. However, intracavitary IL-1β concentrations increased significantly after progesterone was given (U1 = 0.020 ± 0.006 nmol/l; U2 = 0.009 ± 0.003 nmol/l; U3 = 0.089 ± 0.046 nmol/l, P < 0.05). High intracavitary IL-1ra levels were present and non-regulated throughout the hormonal treatment (U1 = 82.139 ± 17.881 nmol/l; U2 = 66,457 ± 16.616 nmol/l; U3 = 69.371 ± 14.754 nmol/l), whereas serum IL-1ra levels were undetectable. Immunohistochemical experiments demonstrated the endometrial origin of IL-1β (epithelium and stroma) and IL-1ra (lumenal epithelium). Intracavitary IL-1α, IL-1β and IL-1ra levels at the apposition phase were higher in patients undergoing oocyte donation compared to IVF patients (0.053 ± 0.029nmol/l versus 0.005 ±0.001 nmol/l; 0.089 + 0.046 versus 0.025 ± 0.011 nmol/l; 69.371 ± 14.754 versus 11.970 ±0.768 nmol/l; P < 0.05, respectively). The present work provides evidence for a paracrine hormonally-regulated presence of the IL-1 system in the human endometrial cavity. Furthermore, intracavitary levels of IL-1α, IL-1β and IL-1ra at the time of embryonic apposition are different, depending upon circulating steroid levels when patients with physiologic and supraphysiological levels are compared, reinforcing the possible role of the IL-1 system as a paracrine effector in human implantation.