[The role of inherited thrombophilia and undifferentiated connective tissue dysplasia syndrome in the pathogenesis of female infertility: A clinical and morphological study].
Impaired endometrial receptivity is a major cause of reproductive losses in in vitro fertilization (IVF) cycles given a normal embryo. Its causes may be associated with many diseases, including inherited thrombophilia (IT) and undifferentiated connective tissue dysplasia syndrome (uCTDS). However, endometrial receptivity remains little studied.


OBJECTIVE
to investigate the morphological and immunohistochemical substrates of impaired endometrial receptivity in women with uCTDS, IT, and their concurrence.


METHODS
Antibodies against ER, PgR, LIF, VEGF, and PAI-1 were used to morphologically and immunohistochemically examine pipelle endometrial biopsy specimens taken from 141 women in the implantation window (on days 6-7 after ovulation). In accordance with their clinical diagnoses, the patients were divided into 4 groups: 1) 13 patients with uCTDS; 2) 100 with IT; 3) 19 with uCTDS and IT; 4) 9 healthy surrogate mothers (a control group). In the examined groups, a total of 145 (90.1%) out of all the IVF protocols were unsuccessful. In the remaining 16 (9.9%) patients without exception, miscarriage started at less than 10 weeks' gestation.


RESULTS
In the implantation window, the endometrium was immature in 101 (83.1%) women and corresponded to late proliferation or early secretion phases; 102 (84.3%) women were also found to have no mature pinopodes, pointing to the fact that the endometrial receptivity was very low. Immunohistochemical examination revealed the lower expression of the receptivity marker LIF in the endometrial surface epithelium and its higher expression in the stroma in the study groups (p < 0.05 for the uCTDS and uCTDS+IT groups) and the higher expression of PAI-1 and VEGF in the epithelium, stroma, and endothelium in the study groups than in the control group (p < 0.05), suggesting the intensity of neoangiogenetic processes and impaired fibrinolysis in these patients.


CONCLUSIONS
uCTDS and IT are risk factors of impaired endometrial receptivity in the pathogenesis of infertility. The manifestations of impaired endometrial receptivity in this case are a decrease in mature pinopodes in the surface epithelium; focal stromal sclerosis; and redistribution of the receptivity marker LIF from the surface epithelium to the stroma, which may be used for diagnosis, prediction, and the development of targeted therapy.
I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow; V.I. Kulakov Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow.
T A
TA
Demura
I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow; V.I. Kulakov Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow.
E A
EA
Kogan
I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow.
A S
AS
Zanozin
OOO 'Doctor Kolosovsky', Moscow.
D Yu
DY
Kolosovsky
V.I. Kulakov Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow.
N M
NM
Faizullina
V.I. Kulakov Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow.
E A
EA
Kalinina
D000328:Adult; D016022:Case-Control Studies; D003240:Connective Tissue Diseases / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D010064:Embryo Implantation; D004717:Endometrium / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007247:Infertility, Female / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D013577:Syndrome; D019851:Thrombophilia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A