Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome

Abstract

Background: Reproductive disorders and infertility are associated with the risk of obstetric complications and have a negative impact on pregnancy outcome. Affected patients often require assisted reproductive technologies (ART) to conceive, and advanced maternal age is a further confounding factor. The challenge is to dissect causation, correlation and confounders in determining how infertility and reproductive disorders individually or together predispose women to poor pregnancy outcomes.

Methods: The published literature, to June 2015, was searched using PubMed, summarizing all evidences concerning the perinatal outcome of women with infertility and reproductive disorders and the potential mechanisms that may influence poor pregnancy outcome.

Results: Reproductive disorders (endometriosis, adenomyosis, polycystic ovary syndrome and uterine fibroids) and unexplained infertility share inflammatory pathways, hormonal aberrations, decidual senescence and vascular abnormalities that may impair pregnancy success through common mechanisms. Either in combination or alone, these disorders results in an increased risk of preterm birth, fetal growth restriction, placental pathologies and hypertensive disorders. Systemic hormonal aberrations, and inflammatory and metabolic factors acting on endometrium, myometrium, cervix and placenta are all associated with an aberrant milieu during implantation and pregnancy, thus contributing to the genesis of obstetric complications. Some of these features have been also described in placentas from ART.

Conclusions: Reproductive disorders are common in women of childbearing age and rarely occur in isolation. Inflammatory, endocrine and metabolic mechanisms associated with these disorders are responsible for an increased incidence of obstetric complications. These patients should be recognized as 'high risk' for poor pregnancy outcomes and monitored with specialized follow-up. There is a real need for development of evidence-based recommendations about clinical management and specific obstetric care pathways for the introduction of prompt preventative care measures.

Keywords: assisted reproductive technologies; endometriosis; inflammation; placenta; polycystic ovary syndrome; pre-eclampsia; preterm birth; sex steroids; unexplained infertility; uterine fibroids.

Figure 1

Hormonal, inflammatory and metabolic factors occurring in the uterus (endometrium, myometrium, cervix) and in placental tissues (trophoblast and membranes) mediate the mechanisms of pregnancy complications in women with PCOS. AR, androgen receptor; ERα, estrogen receptor alpha; SHBG, sex hormone-binding globulin; 3β-HSD-1, 3beta-hydroxysteroid dehydrogenase type 1; IGFBP, insulin-like growth factor-binding protein; IGF-1, insulin-like growth factor type 1; TX, thromboxane; ET, endothelin; NOS, nitric oxide synthase; PGs, prostaglandins; STAT3, signal transducer and activator of transcription 3: TNF-α, tumor necrosis factor-alpha; IL-1, interleukin 1; IL-6, interleukin 6; CXCs, chemokines; MMPs, matrix metalloproteinases; ROS, reactive oxygen species.

Figure 2

Hormonal and inflammatory factors occurring in uterus (endometrium, myometrium, cervix) and in placental tissues (trophoblast and membranes) mediate the mechanisms of pregnancy complications in women with endometriosis and adenomyosis. PR-A, progesterone receptor isoform A; PR-B, progesterone receptor isoform B; CRH, corticotropin-releasing hormone; Ucn1, urocortin 1; COX-2, cyclooxygenase 2; PAR, protease-activated receptor.

Figure 3

Hormonal, inflammatory and metabolic factors occurring in placental tissues (trophoblast and membranes) mediate the mechanisms of pregnancy complications in women with unexplained infertility and requiring ART. UGT, uridine 5′-diphospho (UDP)-glucuronosyltransferase; SULT, sulfotransferase; GLUT1, glucose transporter type 1; GLUT3, glucose transporter type 3; VEGF, vascular endothelial growth factor.