Stanniocalcin-1 in the female reproductive system and pregnancy

Abstract

Background: Stanniocalcin-1 (STC-1) is a widely expressed glycoprotein hormone involved in a diverse spectrum of physiological and pathophysiological processes including angiogenesis, mineral homeostasis, cell proliferation, inflammation and apoptosis. Over the last 20 years, numerous studies have reported STC-1 expression within female reproductive tissues including the uterus, ovaries and placenta and implicated STC-1 in processes such as ovarian follicular development, blastocyst implantation, vascular remodelling in early pregnancy and placental development. Notably, dysregulation of STC-1 within reproductive tissues has been linked to the onset of severe reproductive disorders including endometriosis, polycystic ovary syndrome, poor trophoblast invasion and placental perfusion in early pregnancy. Furthermore, significant changes in tissue expression and in maternal systemic concentration take place throughout pregnancy and further substantiate the vital role of this protein in reproductive health and disease.

Objective and rationale: Our aim is to provide a comprehensive overview of the existing literature, to summarise the expression profile and roles of STC-1 within the female reproductive system and its associated pathologies. We highlight the gaps in the current knowledge and suggest potential avenues for future research.

Search methods: Relevant studies were identified through searching the PubMed database using the following search terms: 'stanniocalcin-1', 'placenta', 'ovary', 'endometrium', 'pregnancy', 'reproduction', 'early gestation'. Only English language papers published between 1995 and 2020 were included.

Outcomes: This review provides compelling evidence of the vital function that STC-1 plays within the female reproductive system. The literature presented summarise the wide expression profile of STC-1 within female reproductive organs, as well as highlighting the putative roles of STC-1 in various functions in the reproductive system. Moreover, the observed link between altered STC-1 expression and the onset of various reproductive pathologies is presented, including those in pregnancy whose aetiology occurs in the first trimester. This summary emphasises the requirement for further studies on the mechanisms underlying the regulation of STC-1 expression and function.

Wider implications: STC-1 is a pleiotropic hormone involved in the regulation of a number of important biological functions needed to maintain female reproductive health. There is also growing evidence that dysregulation of STC-1 is implicated in common reproductive and obstetric disorders. Greater understanding of the physiology and biochemistry of STC-1 within the field may therefore identify possible targets for therapeutic intervention and/or diagnosis.

Keywords: stanniocalcin-1 / STC1 / reproduction / placenta / ovary / endometrium / uterus / pregnancy / decidualisation / implantation.

Figure 1.

A schematic illustration of the proposed regulation and roles of thecal cell-derived STC-1 in granulosa cells and luteal cells in the developing follicle. Demonstrated roles are shown with solid arrows, postulated roles are shown with dashed arrows. cAMP, cyclic adenosine monophosphate; IGF, insulin-like growth factor; PKA, protein kinase A; ROS, reactive oxygen species; STC-1, stanniocalcin-1.

Figure 2.

A schematic overview of the pathway underlying STC-1 secretion from the choriocarcinoma-derived cytotrophoblast cell line, BeWo, under conditions of low oxygen. AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; HIF-2α, hypoxia-inducible factor-2 alpha; mTORC2, mammalian target of rapamycin complex 2; PKA, protein kinase A; STC-1, stanniocalcin-1.