Stanniocalcin-1 in the female reproductive system and pregnancy

Blastocyst implantation is a tightly controlled physiological process which requires complex interactions between the developing embryo and the uterus ( Paria et al. , 2002 ). Dramatic changes in gene expression accompany this process to aid decidualisation and remodelling of the uterine architecture ( Stasko et al. , 2001 ). Several studies have implicated STC-1 in this process in numerous species through the observation of dynamic changes in its gene and protein expression throughout both the decidualisation and implantation processes. The strategies underlying these processes vary significantly across species, thus STC-1 expression and localisation also appear to be species-specific. Herein, the uterine expression patterns and putative roles for STC-1 in decidualisation and implantation in several mammalian species are described. Early studies in mice first suggested a role for STC-1 in decidualisation and blastocyst implantation ( Stasko et al. , 2001 ). Following blastocyst implantation, STC-1 gene expression in the mouse uterus shifts from the uterine epithelium to the mesometrial stromal cells. Between days 6.5–8.5 of pregnancy, STC-1 gene expression then moves to cells of the mesometrial lateral sinusoids and declines thereafter ( Stasko et al. , 2001 ). The localisation of STC-1 protein varies from its gene expression. STC-1 protein is reported to accumulate in epithelial, stromal and decidual cells, as well as in fetal giant trophoblast cells throughout the implantation process. In addition, it localises to decidualising anti-mesometrial cells ( Stasko et al. , 2001 ). The mRNA-protein disparities observed here indicate that STC-1 is transcribed in one cell type and then sequestered by target cells for action, suggestive of a paracrine/autocrine signalling role during these processes in the uterus ( Stasko et al. , 2001 ). The pattern of STC-1 expression during implantation has been further investigated in rats ( Xiao et al. , 2006 ). Here, similar expression patterns to those seen in mice have been reported. In rats, STC-1 mRNA is present in the stromal cells surrounding the implanting blastocyst. It is notable, however, that in pseudopregnant rats, corresponding STC-1 gene expression is not observed suggesting that STC-1 expression in the uterus is specifically induced by developing embryos and implanting blastocysts. This hypothesis is further evidenced by the observation that STC-1 mRNA is maintained at a basal level during an induced delay in implantation but is elevated following termination of the delay. In addition, STC-1 gene and protein expression are concentrated at sites with the implanting blastocyst compared to other uterine segments ( Xiao et al. , 2006 ). In contrast to rodents, studies in sheep have revealed that STC-1 gene expression is confined to endometrial glandular epithelial cells and is induced by progesterone ( Song et al. , 2006 ). Expression is detectable in the endometrial glands from day 16, consistent with the start of blastocyst implantation ( Spencer et al. , 2004 ), to day 120 of gestation and is stimulated by the placental hormones, ovine placental lactogen and ovine growth hormone ( Song et al. , 2006 ). STC-1 protein is also present in the endometrial glands, and is secreted into the uterine lumen where it is detectable in uterine secretions, allantoic fluid and placental areolae which transport uterine gland secretions across the placenta and into the fetal-placental circulation. Secretion of STC-1 from uterine glands into the fetal circulation and allantoic fluid in this manner may suggest an exocrine role in this system ( Song et al. , 2006 ). In pigs, STC-1 mRNA is present exclusively in the luminal epithelium at the uterine-conceptus interface during the period of conceptus attachment prior to implantation, between days 12–25 of pregnancy ( Song et al. , 2009 ). Consistent with observations in sheep, STC-1 expression is also induced by progesterone and is initially stimulated by oestrogen in the luminal epithelium at implantation sites. Expression is later inhibited, however, by the combined effects of oestrogen and progesterone. STC-1 protein is also detectable but is found in uterine luminal fluids ( Song et al. , 2009 ). Although a specific role has yet to be elucidated, it is postulated that in pigs, STC-1 may be involved in implantation through effects on uterine receptivity and remodelling of the trophoectoderm for conceptus elongation ( Song et al. , 2009 ). STC-1 expression in the equine uterus is remarkably similar to that seen in the pig uterus, where increased endometrial STC-1 expression coincides with conceptus attachment ( Kikuchi et al. , 2011 ). STC-1 protein is detectable in uterine luminal fluids, indicating secretion of STC-1 from the endometrial glands towards the conceptus ( Kikuchi et al. , 2011 ), which is consistent with observations in pigs and sheep ( Song et al. , 2006 , 2009 ). In the equine uterus, it is also suggested that STC-1 expression is regulated by conceptus oestrogen ( Kikuchi et al. , 2011 ). As the STC-1 gene lacks any steroid receptor binding sites in its upstream region, it is likely that the effect of steroid hormones on STC-1 expression is indirect ( Kikuchi et al. , 2011 ). STC-1 possesses early growth response factor (Egr) binding sites in its upstream region and, since ligand-activated oestrogen receptors can up-regulate gene transcription indirectly through transcription factors such as the Egr family, it is possible that this represents an indirect mechanism for steroid hormone action on STC-1 expression ( Almeida et al. , 2006 ; Melamed et al. , 2006 ). In addition, other factors present in the equine uterus, such as vascular endothelial growth factor A or hypoxia-inducible factor 1α, can be activated by oestrogen in vitro ( Kazi and Koos, 2007 ; Bake et al. , 2008 ) and are reported to induce expression of STC-1, possibly indicating another indirect mechanism ( Wary et al. , 2003 ; Yeung et al. , 2005 ). It is interesting that the uterine expression of STC-1 during early pregnancy appears to differ amongst species. STC-1 expression in pigs, horses and rodents is detectable earlier than in sheep, from the point of conceptus attachment ( Stasko et al. , 2001 ; Song et al. , 2006 , 2009 ; Xiao et al. , 2006 ; Kikuchi et al. , 2011 ). In pigs, STC-1 expression appears to be limited only to the peri-implantation period of pregnancy, unlike rodents and sheep where expression continues into the later stages of placentation ( Stasko et al. , 2001 ; Song et al. , 2006 , 2009; Xiao et al. , 2006 ). The observed temporal and spatial expression of STC-1 in pigs and horses suggests that STC-1 may play an important role in conceptus attachment during implantation ( Song et al. , 2009 ; Kikuchi et al. , 2011 ), whereas in rodents and sheep, STC-1 may be involved in later stages of implantation and decidualisation. It is intriguing that in bovines, endometrial STC-1 expression does not appear to be pregnancy-specific as comparable expression is detected in the non-pregnant, cyclic uterus ( Muñoz et al. , 2017 ). It is likely that these inter-species differences manifest from intrinsic differences in placental structure and development between species. Despite our knowledge of the role of STC-1 in blastocyst implantation in non-human mammals, its corresponding role in humans has been little studied due to the challenges in investigating human pregnancy in vivo . A 2009 study by Allegra and colleagues is, thus far, the only study to implicate STC-1 in the process of blastocyst implantation in humans. By investigating endometrial gene expression in women undergoing IVF treatment who subsequently became pregnant it was found that STC-1 is one of only six genes which retains homogenous expression during the window of implantation ( Allegra et al. , 2009 ). Confirmation of STC-1 involvement in implantation will, however, require further study. From the numerous studies discussed herein, it appears evident that STC-1 plays a role in the uterus during early pregnancy, particularly during the implantation/peri-implantation period. Therefore, data obtained from studies using genetically engineered mouse models are surprising. In STC-1 null mice, no important change in fertility was detectable ( Chang et al. , 2005 ). It is possible that there may be other gene products capable of fully compensating for STC-1 in this context. The potential for STC-2 to act in this way was investigated in the same study, however, no change in the expression of STC-2 in organs in the STC-1 null mice was detected, suggesting that this is not the compensatory factor ( Chang et al. , 2005 ). In contrast, transgenic overexpression of human STC-1 in mice results in reduced female reproductive capacity ( Varghese et al. , 2002 ). It is unclear what causes this, but from the data on uterine STC-1 expression in mice ( Stasko et al. , 2001 ), it is apparent that dramatic and precise shifts in expression accompany blastocyst implantation, thus, it is postulated that transgenic overexpression may interfere with this tightly controlled process ( Varghese et al. , 2002 ). In addition to its dynamic regulation and putative essential function in establishing a healthy pregnancy, STC-1 has also been implicated in the remodelling of the maternal vasculature which occurs early in pregnancy ( Wallace et al. , 2013 ). During the second half of the menstrual cycle, under the influence of progesterone, highly coiled arteries begin to form at the myometrial-endometrial boundary of the uterus; these are known as spiral arteries ( Ferenczy et al. , 1979 ). These arteries supply blood to the endometrial layer and, during pregnancy, they span the inner myometrium and decidua. During early pregnancy, spiral arteries undergo a unique remodelling process in which they change from small, high resistance vessels to large, low resistance vessels ( Burton et al. , 2009 ). This remodelling results in large diameter vessels which are unresponsive to vasoconstrictors allowing an unimpeded increase in blood flow to the developing foetus ( Osol and Mandala, 2009 ). During the remodelling process, vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are lost from the spiral arteries and are replaced by fetal trophoblast cells ( Pijnenborg et al. , 1983 ; Burton et al. , 1999 ). Trophoblast cells disrupt the interactions of the VSMCs and ECs through processes including apoptosis and dedifferentiation and supplant the vascular cells ( Whitley and Cartwright, 2009 ). The spiral artery remodelling process is completed by 20–22 weeks of gestation ( Sato et al. , 2012 ). Defects in maternal vasculature remodelling have been associated with the onset of several pregnancy complications, including pre-eclampsia, fetal growth restriction and pre-term labour. Although these complications do not manifest until later in pregnancy, it is thought that their pathology is established during the early stages of pregnancy ( Cartwright and Whitley, 2017 ). For example, spiral arteries derived from pre-eclamptic pregnancies have a reduced mean external diameter compared to those from normal pregnancies (200 µm compared to 500 µm) ( Brosens et al. , 1972 ). This defect in vascular remodelling dramatically reduces blood supply to the placenta resulting in poor placental perfusion ( Zhou et al. , 1993 ; Redman and Sargent, 2001 ). Despite our knowledge of insufficient vascular remodelling in early pregnancy, the specific mechanisms underlying the physiology and pathophysiology of the process are poorly understood. A potential role for STC-1 in this process, however, has been suggested. STC-1 was first implicated in the process of spiral artery remodelling following investigation of the role of fetal trophoblast secreted factors on vascular cell gene expression ( Wallace et al. , 2013 ). The use of a three-dimensional spheroid co-culture of ECs and VSMCs to represent an inverted vessel lumen, revealed two-fold up-regulation of STC-1 following incubation with conditioned media from an extravillous trophoblast cell line ( Wallace et al. , 2013 ). The mechanisms underlying the up-regulation of STC-1 within this system are not yet understood, however, it is known that fetal trophoblast cells secrete a range of growth factors and cytokines, including hepatocyte growth factor, vascular endothelial growth factor, interleukin-1β, interleukin-6, platelet-derived growth factor and placental growth factor ( Wallace et al. , 2013 ). It is likely that a number of these factors will act either individually or in synchrony to stimulate STC-1 gene expression from vascular cells and this will require further investigation. Despite clear up-regulation of STC-1 in the remodelling vessel, its specific function has yet to be described. It is evident from the current research that a number of tightly controlled cellular events take place during the vascular remodelling process ( Whitley and Cartwright, 2010 ). The existing literature on the functional roles of STC-1 may suggest its potential mechanisms of action within the remodelling spiral artery. For example, STC-1 has been shown to inhibit the action of inflammatory cytokines, including tumour necrosis factor α ( Chen et al. , 2008 ; Sheikh-Hamad, 2010 ), an important factor in the regulation of vascular cell apoptosis in artery remodelling ( Rastogi et al. , 2012 ). In addition, STC-1 antagonises the activity of vascular reactive factors, including angiotensin II and hepatocyte growth factor ( Zlot et al. , 2003 ; Liu et al. , 2012 ; Moreau et al. , 2012 ). Both factors are known to be present within the environment of the remodelling spiral artery and could influence the behaviour of vascular cells. Furthermore, overexpression of STC-1 has been shown to promote angiogenesis in vivo and in vitro ( Bell et al. , 2001 ; Gerritsen et al. , 2002 ; Liu et al. , 2003 ; He et al. , 2011 ), suggesting that it may have different roles depending on concentration or the local environment. It is crucial to maintain a balance of signals within the remodelling spiral artery to allow vessel change but also apply limits. Therefore, it is possible that altering levels of STC-1 acts as a local control mechanism to prevent excessive remodelling, but this will require further study. The placenta is a highly specialised, pregnancy specific organ that develops rapidly throughout gestation. The expression of placental genes varies significantly during pregnancy, with genes regulating the cell cycle, differentiation, motility and angiogenesis being up-regulated in early pregnancy, whereas genes involved in lipid metabolism, stress response and signal transduction are highly expressed at term ( Winn et al. , 2007 ). Transcriptome profiling of human placental gene expression dynamics from early to mid-gestation has revealed significant expression of STC-1 during this period with a peak of expression during mid-gestation. Interestingly, placental STC-1 expression also remains high at term, but only in complicated pregnancies ( Uusküla et al. , 2012 ). Several single-nucleotide polymorphisms (SNPs) in the STC-1 gene have been identified which appear to directly modulate placental STC-1 transcript levels ( Juhanson et al. , 2016 ). It is possible that these SNPs explain the observed variation in placental STC-1 gene expression levels between normal and complicated pregnancies, but this requires further study ( Juhanson et al. , 2016 ). Although the precise role of placental STC-1 in pregnancy has yet to be elucidated, current findings in the field suggest that it plays a role in maintaining a healthy pregnancy, but may also be implicated in the pathology of pregnancy complications ( Abid et al. , 2020 ). Until recently, the cellular origin of STC-1 in the developing placenta had not been determined. Immunohistochemical staining of placental tissue has now revealed that STC-1 is predominantly expressed in the syncytiotrophoblast and cytotrophoblast cells of the first trimester placenta. STC-1 protein expression is also reported in placental endothelial and stromal cells but at lower expression levels ( Abid et al. , 2020 ). It was also reported that placental cells secrete STC-1 ( Abid et al. , 2020 ) and we are now beginning to understand the mechanisms underlying the regulation of this secretion. Low oxygen conditions (1% O 2 ), combined with induction of intracellular cAMP, have been shown to increase STC-1 secretion from a choriocarcinoma-derived cytotrophoblast cell line (BeWo) ( Abid et al. , 2020 ). In this cell line, elevated intracellular cAMP induces cell fusion and differentiation ( Wice et al. , 1990 ). In vivo , differentiation of trophoblast cells is induced through the same mechanism where cAMP is stimulated by hCG ( Weedon-Fekjær and Taskén, 2012 ). Pharmacological modulation of PKA has revealed that the secretion of STC-1 from BeWo cells is mediated through this pathway ( Abid et al. , 2020 ). Interestingly, elevation of intracellular cAMP alone had no effect on the secretion of STC-1 by BeWo cells, it was only in combination with low oxygen that a significant effect on secretion was observed. Similar data from first trimester chorionic villus tissue shows that STC-1 secretion was greater under conditions of low oxygen ( Abid et al. , 2020 ). Further investigation of the pathways underlying STC-1 secretion under these conditions has shown that this process is mediated through activation of the PI 3 -Kinase/Akt/SGK-1 pathway, primarily through activation of mTORC-2. In addition, inhibition of the transcription factor hypoxia-inducible factor 2α resulted in complete inhibition of STC-1 secretion in this system, suggesting a key role for this factor ( Abid et al. , 2020 ) ( Fig. 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. The observation of increased STC-1 secretion exclusively under low oxygen conditions is significant in relation to the in   vivo situation. In early gestation, the oxygen concentration at the maternal–foetal interface is thought be around 1–2% ( Rodesch et al. , 1992 ). Around the 10th week of pregnancy, however, blood flow to the developing placenta changes significantly due remodelling of the maternal spiral arteries and the loss of trophoblast plugs ( Burton et al. , 2009 ). In pregnancies that later develop complications such as pre-eclampsia or fetal growth restriction, this remodelling is insufficient, resulting in placental under-perfusion and hypoxia ( Redman and Sargent, 2001 ). It is notable that placental STC-1 expression and secretion are increased in pregnancies with these complications ( Uusküla et al. , 2012 ; Abid et al. , 2020 ), therefore it is plausible that low oxygen may be a stimulus for STC-1 expression in the developing placenta. Correspondingly, increased STC-1 expression in response to low oxygen has also been observed in several pathological conditions including cerebral ischaemia ( Zhang et al. , 2000 ), carcinogenesis ( Chang et al. , 2003 ; Liu et al. , 2010 ; Ma et al. , 2015 ) and heart failure ( Sheikh-Hamad et al. , 2003 ). In healthy, non-pregnant individuals, STC-1 is absent or undetectable in the circulation. During pregnancy, however, detectable levels of STC-1 have been reported, and are suggestive of an endocrine role in pregnancy ( Deol et al. , 2000 ). The source of circulating STC-1 in pregnancy is an area of uncertainty in the field. It is postulated that circulating STC-1 may originate from the ovary, due to the coincident rise in ovarian STC-1 gene expression with increased serum STC-1 levels ( Deol et al. , 2000 ). It is also thought, however, that the placenta may be the source of circulating STC-1 due to observed STC-1 secretion from placental cells ( Abid et al. , 2020 ). It is notable that STC-1 remains in the circulation post-partum after the placenta is delivered, therefore, it is conceivable that circulating STC-1 could originate from both the placenta and the ovaries, or that the tissue origin changes post-partum, perhaps to support the physiology of lactation. In pregnancies complicated by conditions whose aetiology is thought to occur in the first trimester, such as pre-eclampsia, fetal growth restriction and gestational diabetes, third trimester and post-partum serum levels of STC-1 are even further elevated ( Uusküla et al. , 2012 ; Abid et al. , 2020 ). This is consistent with increased secretion of STC-1 seen in first trimester placentas derived from pregnancies at risk of developing pre-eclampsia ( Abid et al. , 2020 ). To fully understand the origin and pattern of STC-1 release into the circulation during pregnancy and pregnancy complications, however, more comprehensive analysis of maternal serum is required. As the ovarian STC-1 is structurally distinct ( Paciga et al. , 2002 ), it is plausible that mass spectrometric analysis of serum could identify the tissue-origin of circulating STC-1. Furthermore, the presence of STC-1 in the circulation in women during pregnancy has only been investigated in the third trimester and post-partum ( Uusküla et al. , 2012 ; Juhanson et al. , 2016 ; Abid et al. , 2020 ), therefore it is unclear at which stage of pregnancy STC-1 is released into the bloodstream. To understand the pattern of STC-1 release into the circulation in human pregnancy, longitudinal studies on maternal serum are required.

Stanniocalcin (STC) is a homodimeric glycoprotein first isolated in bony fish ( Wagner et al. , 1986 ). It is secreted by the corpuscles of Stannius, small endocrine glands located on the ventral surface of the kidneys ( Stannius, 1839 ). The function of these glands was elucidated in 1964 when surgical removal resulted in hypercalcaemia ( Fontaine, 1964 ). In the late 1980s, the anti-hypercalcaemic factor secreted by the corpuscles of Stannius was purified and identified as STC ( Wagner et al. , 1986 ; Lafeber et al. , 1988 ). In the 1990s, a mammalian orthologue was discovered following the successful cloning of mouse and human cDNAs by two independent groups ( Chang et al. , 1995 , 1996 ; Olsen et al. , 1996 ). The amino acid sequence of this orthologue shows ∼61% identity and ∼73% similarity with various fish STCs ( Chang et al. , 1995 ). Moreover, 2 years after the discovery of mammalian STC, several research groups identified a second member of the mammalian STC family ( Chang and Reddel, 1998 ; DiMattia et al. , 1998 ; Ishibashi et al. , 1998 ). This finding resulted in the renaming of mammalian STC as STC-1 and the newly identified protein as STC-2 ( Chang and Reddel, 1998 ). Human STC-1 cDNA encodes a protein of 247 amino acids ( Chang et al. , 1995 ). When compared to fish STC, the first 204 amino acids of human STC-1 show 92% similarity to that of salmon, however, the last 43 residues at the C-terminus differ immensely ( Chang et al. , 2003 ). In contrast, human STC-2 encodes a protein of 302 amino acids which shows just 34% identity to both human STC-1 and eel STC, with the greatest sequence similarity present at the N-terminus ( Chang et al. , 2003 ). At this terminus, a conserved cysteine motif is found in both fish and human STCs. In STC-1, there are 11 cysteine residues with the same spacing as those in fish STCs ( Butkus et al. , 1987 ; Wagner et al. , 1992 ). STC-2 possesses 15 cysteine residues, but only 10 of which have the same spacing as fish STC and STC-1 ( Moore et al. , 1999 ). During translation of the protein, 10 out of the 11 cysteines form intrachain disulphide linkages and the 11th cysteine residue functions in forming the interchain dimer ( Trindade et al. , 2009 ), allowing STC-1 to exist as a homodimer in its native state ( Lafeber et al. , 1988 ). The lack of spatial conservation of the 11th cysteine residue in STC-2 compared to fish STC/STC-1, combined with the presence of four additional cysteine residues in this protein, leads to the prediction that STC-2 has a different tertiary structure when compared with other STCs. Despite some structural similarities between both STC-1 and STC-2, there is no evidence, thus far, to suggest that these proteins are capable of heterodimerisation ( Joshi, 2020 ). Another defining feature of STC-1, which is also conserved amongst the STCs, is the presence of an N-linked glycosylation consensus sequence (Asn-X-Thr/Ser). In STC-1, this is present at residues 62–64; consistent with the position of this sequence in fish STC ( Butkus et al. , 1987 ; Wagner et al. , 1992 ). STC-1 appears to exist in several forms; the predicted molecular weight of STC-1 is 27 kDa, however, studies have pointed to the existence of di- or multimers ( Zhang et al. , 1998 ; Paciga et al. , 2002 , 2005a ). The dimeric 56 kDa form of STC-1 is known as STC50 ( Paciga et al. , 2005b ). In addition, a number of higher molecular weight STC-1 variants have been identified in ovarian cells, adrenocortical cells and adipocytes, and are collectively referred to as ‘big STC’. Within this category, at least three molecular weights: 84, 112 and 135 kDa have been described ( Paciga et al. , 2002 , 2005a ). STC-1 is secreted from most cells and contains a signal peptide sequence of ∼24 amino acids and a pro-sequence of ∼15 amino acids, both of which a processed to yield the mature forms of the protein ( Moore et al. , 1999 ). In most cell types, STC-1 is produced in large amounts intracellularly in lightly glycosylated forms, however, when secreted, STC-1 is highly glycosylated and phosphorylated by protein kinase C ( Jellinek et al. , 2000 ). STC-1 has a wide expression pattern in mammals, with reported expression in many tissues including the heart, lungs, liver, adrenal gland, kidney, ovary, prostate, colon, bone and spleen ( Chang et al. , 1995 ; Olsen et al. , 1996 ; Varghese et al. , 1998 ; Yoshiko and Aubin, 2004 ; Liu et al. , 2010 ; Law et al. , 2011 ). In humans, the STC-1 gene is expressed predominantly as a 4 kb transcript and the highest expression levels are found in the ovary, kidney, prostate and thyroid ( Moore et al. , 1999 ). Consistent with its wide expression profile, STC-1 appears to act in a pleiotropic manner in mammalian systems. It has been implicated in a diverse range of processes including mineral homeostasis ( Olsen et al. , 1996 ), angiogenesis ( He et al. , 2011 ; Law and Wong, 2013 ), organogenesis ( Jiang et al. , 2000 ; Stasko and Wagner, 2001 ), cell proliferation ( Bai et al. , 2017 ), apoptosis ( Kim et al. , 2013 ), retinal degeneration ( Roddy et al. , 2012 ), cerebral ischaemia ( Zhang et al. , 2000 ), inflammation ( Mohammadipoor et al. , 2016 ), tumourigenesis ( Liu et al. , 2010 ) and anti-oxidative activity ( Kim et al. , 2013 ; Wu et al. , 2014 ; Bonfante et al. , 2020 ). In addition, numerous studies have highlighted the role of STC-1 in the physiology and pathophysiology of the female reproductive system. These studies have outlined the wide expression of STC-1 amongst female reproductive tissues including the uterus ( Stasko et al. , 2001 ; Xiao et al. , 2006 ; Allegra et al. , 2009 ), placenta ( Uusküla et al. , 2012 ; Juhanson et al. , 2016 ; Abid et al. , 2020 ), and the developing maternal vasculature in early pregnancy ( Wallace et al. , 2013 ). Amongst all female reproductive tissues, the greatest expression is seen in the ovary ( Varghese et al. , 1998 ; Deol et al. , 2000 ). STC-1 expression is virtually undetectable in the male testis ( Varghese et al. , 1998 ; Deol et al. , 2000 ), indicating that it has a specific role in female reproduction. This review will provide an overview of the existing literature on the expression and putative functions of STC-1 within female reproduction and postulate future avenues of research ( Table I ). Table I A summary of the expression pattern and roles of stanniocalcin-1 (STC-1) in different reproductive tissues across a number of species. Note : Postulated roles are in grey text.

This review was prepared by systematically searching the literature using the PubMed database with the search terms: ‘stanniocalcin-1’, ‘placenta’, ‘ovary’, ‘endometrium’, ‘pregnancy’, ‘reproduction’, ‘early gestation’. No restrictions were placed on the year published, but a focus was placed on papers published between 1995 and 2020 and only English language papers were included.

STC-1 was first implicated in the field of female reproduction over 20 years ago, but despite this, we are only now beginning to understand the mechanisms underlying its regulation in female reproductive tissues and its specific functions in this system. The current data suggest dynamic regulation of STC-1 within ovarian cells and indicate a paracrine system in which STC-1 is sequestered to target cells for action ( Deol et al. , 2000 ; Luo et al. , 2004 ; Basini et al. , 2010 ). STC-1 appears to function in the process of ovarian follicular development as well as in modulating ovarian steroidogenesis ( Paciga et al. , 2003 ; Luo et al. , 2004 ; Baioni et al. , 2011 ; Jepsen et al. , 2016 ). In the human endometrium, the specific function of STC-1 has yet to be elucidated, however, clear dysregulation of STC-1 in endometrial pathologies indicates a further requirement for study in this area ( Aghajanova et al. , 2016 ; Khatun et al. , 2020 ). Furthermore, uterine expression of STC-1 in early gestation may highlight a key role for this protein in the physiology and pathophysiology of pregnancy. Coincident expression of STC-1 during blastocyst implantation in most mammalian species, including humans, suggests its involvement in the establishment of pregnancy ( Stasko et al. , 2001 ; Song et al. , 2006 , 2009 ; Xiao et al. , 2006 ; Allegra et al. , 2009 ; Kikuchi et al. , 2011 ). Moreover, expression of STC-1 in the developing placenta and altered expression in complicated pregnancies highlights the requirement of STC-1 for maintenance of a healthy pregnancy but suggests that its expression must be tightly regulated ( Uusküla et al. , 2012 ; Juhanson et al. , 2016 ; Abid et al. , 2020 ). It is evident that expression of STC-1 in most cells types is mediated through the PKA pathway and is induced by cAMP ( Paciga et al. , 2002 , 2004 ; Aghajanova et al. , 2016 ; Abid et al. , 2020 ; Khatun et al. , 2020 ). This is interesting as it indicates consistent regulation mechanisms amongst reproductive cell types, which could aid future research in this area. The present data, combined with the known roles of STC-1 in diverse biological processes, are strongly suggestive of a pivotal role in female reproduction. The obvious limitations in studying the human reproductive system in vivo and the lack of adequate models have hindered our progression in the field. It is clear, however, that further research is required to elucidate the specific roles of STC-1 within various reproductive tissues, as this will help shed light on the pathogenesis of reproductive pathologies in which STC-1 is dysregulated.

No new data were generated or analysed in support of this research.