{"paper_id":"d4e3734f-d0fa-40b2-99f1-7446201cc54b","body_text":"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 ).\nHuman 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 ).\nSTC-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 ).\nSTC-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 ).\nConsistent 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 ).\nTable I A summary of the expression pattern and roles of stanniocalcin-1 (STC-1) in different reproductive tissues across a number of species.\nNote : Postulated roles are in grey text.\n\nThis 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.\n\nEarly studies in mice revealed that the highest levels of STC-1 expression are found in the ovary where expression commences postnatally and rises throughout development ( Deol  et al. , 2000 ). Within the adult mouse ovary, STC-1 gene and protein expression are detectable in the secondary interstitial and theca interna cells, however, only STC-1 protein expression is found in oocytes and corpus luteal cells ( Varghese  et al. , 1998 ). The discordance between gene and protein expression observed here could be indicative of a mechanism in which oocytes and corpus luteal cells do not express the STC-1 gene but are targets for STC-1 and therefore sequester the protein ( Varghese  et al. , 1998 ).\nAlthough ovarian STC-1 gene expression remains constant throughout the oestrous cycle in mice, STC-1 protein expression increases during metoestrus I in the corpus luteum and declines thereafter ( Deol  et al. , 2000 ). During pregnancy and the post-partum period in mice, ovarian STC-1 mRNA increases 15-fold, reaching a peak between days 10–14 of gestation before dropping sharply at the time of birth and rising again postpartum ( Deol  et al. , 2000 ). Co-incident with the rise in STC-1 gene expression, STC-1 protein levels also increase, and the protein is detectable in the circulation for the first time. Within the ovary, the spatial distribution of STC-1 mRNA remains relatively constant, where it is detectable in the interstitium and thecal compartment. In contrast, STC-1 protein localises to the oocytes and thecal cells of primary and secondary follicles, as well as to interstitial cells and corpora lutea ( Deol  et al. , 2000 ). The active regulation of ovarian STC-1 expression during gestation suggests a key role for STC-1 in the physiology of this process. It is noteworthy that STC-1 is the only secreted protein produced by the ovarian thecal interstitial compartment that is significantly up-regulated during mouse pregnancy ( Deol  et al. , 2000 ).\nOvarian STC-1 expression has also been reported in pigs, rats and bovines ( Worthington  et al. , 1999 ;  Paciga  et al. , 2002 ). Although not fully characterised in rats and bovines, in pigs, STC-1 protein expression was reported in follicular fluid and was shown to be produced by granulosa cells ( Basini  et al. , 2010 ), while STC-1 gene expression was detectable in the thecal layer of antral follicles, consistent with findings in mice, rats and bovines ( Varghese  et al. , 1998 ;  Paciga  et al. , 2002 ). During follicle development, STC-1 expression in thecal layer cells in the swine ovaries begins to decrease, whilst STC-1 expression in granulosa cells increases ( Basini  et al. , 2010 ). Granulosa cell STC-1 expression is also significantly increased under conditions of hypoxia and anoxia ( Basini  et al. , 2010 ). The increase in STC-1 expression in ovarian follicles during follicular development observed here, combined with its induction under conditions of oxygen deprivation are strongly indicative of a role for STC-1 in ovarian follicle physiology, especially as progressive hypoxia is established during follicle growth ( Basini  et al. , 2010 ).\nThe mechanisms underlying the regulation of STC-1 expression in the mammalian ovary are beginning to be appreciated. In a superovulation mouse model, administration of human chorionic gonadotropin (hCG), which mimics the effects of luteinising hormone (LH) and induces ovulation, resulted in a 2.5-fold increase in steady-state STC-1 mRNA levels, suggesting that STC-1 may be regulated by LH ( Deol  et al. , 2000 ). In rat and bovine thecal interstitial cells, hCG also stimulates STC-1 secretion ( Paciga  et al. , 2002 ). This response was mimicked by treatment with forskolin, suggesting that STC-1 regulation is mediated through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. The stimulatory effect of hCG on STC-1 expression was only completely suppressed following inhibition of PKA, demonstrating the requirement for PKA activation in hCG-induced STC-1 expression in thecal interstitial cells ( Paciga  et al. , 2002 ).\nThe ovarian form of STC-1 is physically distinct and has been referred to as ‘big STC’ ( Paciga  et al. , 2002 ). In light of the discovery of STC-2 in 1998 ( Chang and Reddel, 1998 ), big STC will hereafter be referred to as big STC-1 for clarity. Cellular and secreted STC-1 from thecal interstitial cells are substantially larger than STC50 which is found in other mammalian tissues. In the native state, STC-1 derived from thecal interstitial cells comprises three molecular mass species of 84, 112 and 135 kDa. Although still uncertain, it was postulated that the increased mass may be due to post-translational modifications, including glycosylation ( Paciga  et al. , 2002 ). However, enzymatic treatment of thecal interstitial cell-derived STC-1 to remove N-glycosylation had no effect, indicating that the mass variation is not due to differential glycosylation ( Paciga  et al. , 2002 ). Chemical reduction of big STC-1 resulted in a 45 kDa species, implying that the three molecular masses are polymers of two or more subunits which are stabilised by disulphide linkages. It is hypothesised that the unique structure of ovarian STC-1 may explain its presence in the circulation during gestation and lactation due to differences in clearance kinetics between big STC-1 and STC50 ( Paciga  et al. , 2002 ).\nAlthough STC-1 receptors in reproductive tissues have been little studied, ovarian big STC-1 receptors have been described ( Paciga  et al. , 2003 ). Through the use of an STC-1 alkaline phosphatase fusion protein, composed of mouse STC-1 cDNA fused to the human placental alkaline phosphatase gene ( McCudden  et al. , 2002 ;  Paciga  et al. , 2003 ), high concentrations of STC-1 receptors have been identified in cultured bovine luteal cells. Within these cells, significant populations of receptors have been found in cholesterol/lipid storage droplets ( Paciga  et al. , 2003 ). Some targeting to the luteal cell plasma membrane is also evident, but the affinity of the plasma membrane receptor is 10-fold lower than that of the cholesterol/lipid storage droplets receptor ( Paciga  et al. , 2003 ). This receptor-mediated targeting in luteal cells provides an explanation for the observed discordances in the patterns of STC-1 mRNA and protein distribution in ovarian cells. For example, although both STC-1 gene and protein expression are detectable in the thecal interstitial compartment in mice, rats and bovines ( Varghese  et al. , 1998 ;  Deol  et al. , 2000 ;  Paciga  et al. , 2002 ), only STC-1 protein expression is present in oocytes and corpus luteal cells ( Varghese  et al. , 1998 ;  Deol  et al. , 2000 ), thus, it is postulated that oocytes and luteal cells may be targets for STC-1 in this case and sequester the protein ( Varghese  et al. , 1998 ).\nAlthough  in vivo  luteal cells do not express the STC-1 gene, when isolated and maintained in culture, STC-1 gene expression can be induced ( Paciga  et al. , 2004 ). In this context, bovine luteal cells are capable of expressing and secreting big STC-1 similarly to thecal interstitial cells ( Paciga  et al. , 2004 ). Unlike in thecal interstitial cells, big STC-1 production by luteal cells is not regulated by LH but is regulated by prostaglandin E 2 . Similar to LH-induced STC-1 expression from thecal interstitial cells, positive regulation of STC-1 expression in luteal cells is mediated through the PKA pathway ( Paciga  et al. , 2004 ).\nNegative regulation of STC-1 expression in luteal cells is achieved by sex steroids; both progesterone and oestradiol suppress STC-1 release from luteal cells and STC-1 expression and secretion are reduced to undetectable levels in the presence of androstenedione ( Paciga  et al. , 2004 ). Both progesterone and oestradiol are autocrine regulators of luteal cell function  in vivo  ( Okuda  et al. , 2001 ;  Berisha  et al. , 2002 ;  Cassar  et al. , 2002 ;  Van Den Broeck  et al. , 2002a , b ), thus, it is possible that these steroids act in concert  in vivo  to suppress luteal cell STC-1 production ( Paciga  et al. , 2004 ). Moreover,  in vivo  luteal cells are in close proximity to the source of androgens, such as androstenedione, which may further explain the observed absence of STC-1 in luteal cells in the intact ovary ( Paciga  et al. , 2004 ). Though it will require further study to fully understand the regulation of luteal cell STC-1 expression  in vivo , it is feasible that STC-1 production in this context is only suppressed under conditions of high sex steroid production, however, when these levels are reduced, for example in the luteal phase of the oestrous cycle or after parturition ( Kanchev and Dobson, 1976 ;  Mostl  et al. , 1981 ), luteal cell STC-1 production could take place  in vivo  ( Paciga  et al. , 2004 ).\nAlthough the regulation of STC-1 expression in luteal cells  in vivo  is not fully understood, it is apparent that thecal interstitial cell-derived STC-1 may be sequestered by luteal cells  in vivo  as they contain high levels of the STC-1 protein ( Varghese  et al. , 1998 ). It appears that this relates to a role in progesterone synthesis. Basal and hCG-stimulated progesterone secretion from luteal cells is significantly decreased by big STC-1 ( Paciga  et al. , 2003 ). Consistent with the requirement for PKA activation in hCG-induced expression of STC-1 in thecal interstitial cells ( Paciga  et al. , 2002 ), big STC-1 receptors in luteal cells are up-regulated in response to PKA activation ( Paciga  et al. , 2003 ). Thus, it is conceivable that  in vivo  big STC-1 may be targeted to luteal cells for the purpose of decreasing PKA-activated steroidogenesis ( Paciga  et al. , 2003 ) ( Fig. 1 ).\nA 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.\nIn addition to its role in modulating steroidogenesis in luteal cells, thecal interstitial cell-derived STC-1 has also been implicated in ovarian follicular development ( Luo  et al. , 2004 ). Similar to the observed effects in bovine luteal cells, STC-1 causes a decrease in gonadotropin-induced progesterone production in granulosa cells ( Luo  et al. , 2004 ). Treatment of rat granulosa cells with recombinant N-glycosylated STC-1 resulted in suppression of FSH-induced progesterone biosynthesis and LH receptor expression but, had little effect on oestradiol production ( Luo  et al. , 2004 ) ( Fig. 1 ). Specific inhibition of progesterone biosynthesis without effect on oestrogen production in this way has also been observed in other ovarian paracrine factors which are postulated as luteinisation inhibitors ( Falck, 1959 ;  Smith  et al. , 1975 ). It is, therefore, possible that STC-1 acts as a luteinisation inhibitor within ovarian follicles, but this will require further investigation. Treatment of rat granulosa cells with STC-1 also results in a decrease in expression of CYP11A mRNA, a rate-limiting enzyme in progesterone biosynthesis ( Zlotkin  et al. , 1986 ;  Goldring  et al. , 1987 ;  Oonk  et al. , 1990 ), and this is the possible mechanism through which STC-1 mediates an effect on progesterone production in granulosa cells ( Luo  et al. , 2004 ). To induce these cell-specific effects, STC-1 likely binds to several high specificity and affinity receptors located on the plasma membrane of granulosa cells, and when inside the cell, STC-1 acts downstream of adenylyl cyclase in the cAMP/PKA pathway to exert its effects on progesterone biosynthesis and LH receptor induction ( Luo  et al. , 2004 ).\nThese findings are indicative of a follicular paracrine system in which thecal interstitial-derived STC-1 acts to dampen gonadotropin-induced granulosa cell differentiation ( Luo  et al. , 2004 ). For STC-1 to act in this inhibitory manner  in vivo , it is clear that stringent regulation of its expression must occur to permit granulosa cell differentiation. It was demonstrated that gonadotropin treatment of thecal interstitial cells suppresses STC-1 expression, suggesting a mechanism in which prior suppression of thecal interstitial STC-1 by gonadotropins is required to allow gonadotropin-induced granulosa cell differentiation ( Luo  et al. , 2004 ). However, previous studies also report stimulation of STC-1 expression in thecal interstitial cells following gonadotropin treatment ( Deol  et al. , 2000 ;  Paciga  et al. , 2002 ), contrary to the gonadotropin-induced suppression of STC-1 from thecal interstitial cells reported by Luo  et al.  (2004). It is possible that differences in methodology could contribute to this discrepancy, therefore, further research is required to understand the regulation of STC-1 expression in thecal interstitial cells.\nAs well as modulating granulosa cell differentiation during ovarian follicular development, STC-1 has also been implicated in the regulation of granulosa cell redox status ( Baioni  et al. , 2011 ). It is thought that the balance of pro-oxidant/anti-oxidant factors within the ovarian follicle plays an important role in folliculogenesis ( Basini  et al. , 2008 ) and that some reactive oxygen species (ROS) induce the expression of genes involved in oocyte maturation and follicular development ( Behrman  et al. , 2001 ;  Agarwal  et al. , 2005 ). In granulosa cells, STC-1 stimulates the production of superoxide anion ( Baioni  et al. , 2011 ), a ROS implicated in modulating ovarian steroidogenesis ( Sawada and Carlson, 1996 ;  Jain  et al. , 2000 ;  Behrman  et al. , 2001 ) and in inducing ovulation ( Behrman  et al. , 2001 ;  Fujii  et al. , 2005 ). The process through which STC-1 stimulates superoxide anion production is unclear; however, as STC-1 is known to have stimulatory effects on the mitochondrial electron transport chain ( Ellard  et al. , 2007 ), and the mitochondria are the main sites of superoxide anion generation ( Murphy, 2009 ), it is possible that the action of STC-1 on mitochondria could explain this effect ( Baioni  et al. , 2011 ). Although STC-1 does not affect the activity of superoxide dismutase, which catalyses the dismutation of superoxide anion to hydrogen peroxide, it has been shown to influence both catalase and peroxidase which scavenge hydrogen peroxide ( Baioni  et al. , 2011 ). High concentrations of STC-1 stimulate catalase activity, thereby reducing levels of hydrogen peroxide. Conversely, elevated levels of STC-1 result in a decrease in peroxidase activity, potentially caused by the catalase-mediated reduction in its substrate, hydrogen peroxide ( Baioni  et al. , 2011 ). These findings suggest that STC-1 may play an important role in ROS homeostasis in granulosa cells during folliculogenesis which may be essential to regulate their activity ( Baioni  et al. , 2011 ) ( Fig. 1 ), but the specific mechanisms underlying these processes, as well as their direct effect on granulosa cell function remain to be elucidated.\nThe insulin-like growth factor (IGF) system is involved in several physiological ovarian functions including follicular growth, steroidogenesis and ovulation ( Kwintkiewicz and Giudice, 2009 ). IGF signalling is regulated by the actions of the metzincin metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A) ( Oxvig, 2015 ) which is known to be secreted from granulosa cells ( Conover  et al. , 2001 ). PAPP-A cleaves a subset of IGF binding proteins, counteracting their inhibitory effects and causing release of bioactive IGF ( Oxvig, 2015 ).  In vitro , STC-1 inhibits PAPP-A proteolytic activity through non-covalent, high affinity binding ( Kløverpris  et al. , 2015 ). More recently, it has been established that these protein interactions also take place  in vivo  within human ovaries ( Jepsen  et al. , 2016 ).\nCoincident expression of both PAPP-A and STC-1 is evident throughout follicular development; PAPP-A and STC-1 are localised together in the primordial, late primary and antral follicles ( Jepsen  et al. , 2016 ). Following follicle stimulation with hCG, the correlation between the intrafollicular concentration of PAPP-A and its activity is altered. hCG stimulation results in an increase in the intrafollicular concentration of PAPP-A, whilst a decrease in its activity is observed ( Jepsen  et al. , 2016 ). Inhibitory complexes between PAPP-A and STC-1 are detectable in follicular fluid at this stage, explaining the decline in PAPP-A activity, despite an increase in its concentration ( Jepsen  et al. , 2016 ). STC-2 is also expressed concurrently with STC-1 and PAPP-A and is found to form covalent inhibitory complexes with PAPP-A in follicular fluid ( Jepsen  et al. , 2016 ). The finding of native complexes between PAPP-A and STC-1/2 in follicular fluid is strongly indicative of a model in which STC-1/2 inhibit the actions of PAPP-A, thus resulting in a decrease in bioactive IGF release ( Jepsen  et al. , 2016 ). IGF activity in the mammalian ovaries has been linked to follicular growth via stimulation of the mitotic activity of granulosa cells ( Kadakia  et al. , 2001 ;  Spicer and Aad, 2007 ). At the midcycle peak, however, granulosa cell proliferation ceases, consistent with the decrease in PAPP-A activity in the follicular fluid ( Jepsen  et al. , 2016 ). Thus, it is conceivable that STC-1/2 may be involved in the decline in granulosa cell proliferation during this stage of folliculogenesis through their actions in inhibiting PAPP-A ( Jepsen  et al. , 2016 ) ( Fig. 1 ). It remains to be determined whether STC-1/2-mediated inhibition of PAPP-A occurs in tissues other than the ovary.\nThe human endometrium is a dynamic tissue which undergoes a number of important histological and structural changes throughout the menstrual cycle in preparation for embryo implantation and subsequent shedding and regeneration in non-conception cycles ( Talbi  et al. , 2006 ). Endometrial STC-1 expression has been described in several mammals, including rats, pigs, sheep and horses ( Song  et al. , 2006 ,  2009 ;  Xiao  et al. , 2006 ;  Kikuchi  et al. , 2011 ). STC-1 expression in the human endometrium has been more recently described ( Aghajanova  et al. , 2016 ;  Khatun  et al. , 2020 ).\nSeveral high-throughput gene expression profiling studies have implicated STC-1 in human endometrial functions and report fluctuating tissue expression levels throughout the menstrual cycle. Endometrial expression of STC-1 is high during the mid-secretory phase (MSE) ( Talbi  et al. , 2006 ;  Aghajanova  et al. , 2016 ;  Boggavarapu  et al. , 2016 ;  Suhorutshenko  et al. , 2018 ), correlating with the expression of receptivity markers during the window of implantation ( Allegra  et al. , 2009 ). Aberrant endometrial expression of STC-1 has also been implicated in hypoxia-mediated abnormal uterine bleeding of long-acting progestin-only contraceptive users ( Shapiro  et al. , 2015 ). The specific expression pattern and cellular localisation of STC-1 in the human endometrium in both normal and diseased states have been poorly studied and the existing literature suffers from restricted sample sizes. The findings, however, may still be clinically relevant but highlight the need for further research in this area.\nEndometriosis is an oestrogen-dependent gynaecological condition characterised by chronic inflammation and the presence and growth of ectopic endometrial tissue ( Hickey  et al. , 2014 ). It affects between 10% and 15% of reproductive aged women and is often associated with severe and chronic pain and infertility ( Mehedintu  et al. , 2014 ). Despite its prevalence, the aetiology of endometriosis is poorly understood. Altered endometrial expression of STC-1 in endometriosis has been described ( Aghajanova  et al. , 2016 ).\nIn healthy women, endometrial STC-1 gene expression fluctuates throughout the menstrual cycle ( Aghajanova  et al. , 2016 ). In the endometrium of women with endometriosis, however, STC-1 gene expression is significantly increased in MSE compared to the proliferative phase (PE) or early secretory phase (ESE). Interestingly, endometrial STC-1 gene expression in PE and MSE is 2-fold higher in women with endometriosis compared to healthy women ( Aghajanova  et al. , 2016 ). Although not reported for women with endometriosis, up-regulation of STC-1 protein in endometrial fluid in MSE compared to ESE is observed in healthy women ( Aghajanova  et al. , 2016 ). Abundance of STC-1 in the secretome of receptive MSE endometrium is highly indicative of a role in the process of implantation ( Aghajanova  et al. , 2016 ), but further studies are required to confirm this role in the human endometrium.\nIn terms of cellular localisation in the MSE human endometrium, STC-1 protein is expressed in the cytoplasm of epithelial and stromal cells from both women with and without endometriosis ( Aghajanova  et al. , 2016 ). In the endometrium of healthy women, STC-1 protein expression appears higher in the luminal epithelium and stroma compared to the glandular epithelium. In the endometrium of women with endometriosis, no difference in STC-1 protein expression was detectable between epithelial cells, however, endometrial stromal cell (eSC) expression of STC-1 was reduced in endometriosis compared to healthy cells ( Aghajanova  et al. , 2016 ).\nIn endometrial stromal fibroblasts decidualised  in vitro  with cAMP, STC-1 gene expression was dramatically up-regulated over 230-fold in healthy women, however, in women with endometriosis, only a 45-fold increase is observed ( Aghajanova  et al. , 2016 ). Of note, STC-1 gene expression is not significantly affected in endometrial stromal fibroblasts decidualised with oestradiol and progesterone in either the healthy or endometriosis group, suggesting that endometrial STC-1 expression is not regulated by sex steroids ( Aghajanova  et al. , 2016 ), consistent with findings in the equine endometrium ( Kikuchi  et al. , 2011 ). It does appear evident, however, that STC-1 expression in endometrial stromal fibroblasts is induced by cAMP and therefore may be mediated though the PKA pathway, but confirmation of this will require further investigation. The observed reduction in the up-regulation of STC-1 in cAMP-decidualised endometrial stromal fibroblasts from women with endometriosis may be indicative of a role in the pathogenesis of decidualisation defects ( Aghajanova  et al. , 2016 ).\nIn addition to endometriosis, STC-1 has also been implicated in the pathology of polycystic ovary syndrome (PCOS) ( Khatun  et al. , 2020 ). PCOS is a common endocrine disorder which affects 8–12% of women of reproductive age. It is characterised by oligo-anovulation, hyperandrogenism and dysregulated metabolism ( Teede  et al. , 2018 ). Moreover, women with PCOS present with subfertility and are at increased risk of developing pregnancy complications as well as endometrial cancer ( Piltonen  et al. , 2013 ;  Katulski  et al. , 2015 ;  Palomba  et al. , 2015 ;  El Hayek  et al. , 2016 ;  McDonnell and Hart, 2017 ). Given the endometrial expression of STC-1, and its link to modulation of hypoxic and inflammatory responses essential for normal endometrial physiology ( Westberg  et al. , 2007a , b ;  Mohammadipoor  et al. , 2016 ), it is postulated that STC-1 may play a role in the pathogenesis of PCOS.\nData obtained from the investigation of endometrial biopsy samples has revealed increased endometrial expression of STC-1 mRNA in MSE and late secretory phase (LSE) in both healthy women and those with PCOS ( Khatun  et al. , 2020 ). In younger women with a more severe PCOS phenotype and higher BMI, STC-1 gene expression did not increase in the secretory phase as it did in the other groups. STC-1 protein expression increased from PE to LSE in stromal cells, but only in healthy women and not in those with PCOS, which is potentially indicative of a stromal cell defect in women with PCOS ( Khatun  et al. , 2020 ). Further investigation of eSCs challenged with cAMP, previously established as an inducer of STC-1 expression, has revealed that eSCs from healthy women displayed a strong increase in STC-1 expression ( Khatun  et al. , 2020 ). eSCs from women with PCOS showed a significantly smaller increase in expression of STC-1 in response to cAMP compared to that in eSCs from healthy controls. Furthermore, reduced basal PKA activity was demonstrated in eSCs from women with PCOS, suggesting a defect in cAMP-mediated PKA signalling in PCOS stromal cells ( Khatun  et al. , 2020 ). In healthy women, STC-1 expression from eSCs was also stimulated under hypoxic conditions ( Khatun  et al. , 2020 ). In contrast, STC-1 expression in eSCs from women with PCOS was not triggered by hypoxia and its secretion from eSCs was also reduced in these conditions ( Khatun  et al. , 2020 ). As hypoxia is a crucial factor in embryo implantation ( Daikoku  et al. , 2003 ;  Matsumoto  et al. , 2018 ), it is possible that the observed impairment in STC-1 expression under these conditions could contribute to the subfertility associated with PCOS.\nThe role of obesity in influencing endometrial STC-1 expression has also been established. Increased secretory phase endometrial STC-1 expression is present in overweight/obese women compared to women with a lower BMI, however, these BMI-specific differences are not apparent in women with PCOS ( Khatun  et al. , 2020 ). Elevated STC-1 expression in the secretory phase endometrium in overweight/obese women suggests that obesity may be a stress factor which leads to the induction of endometrial STC-1 expression, however, this mechanism appears absent in women with PCOS ( Khatun  et al. , 2020 ). A 3-month lifestyle intervention, commonly recommended as the first-line therapy for women with PCOS and obesity ( Teede  et al. , 2018 ), was unable to restore STC-1 expression in the PCOS endometrium, corroborating the report of impaired STC-1 regulation in the PCOS endometrium, regardless of BMI ( Khatun  et al. , 2020 ).\n\nBlastocyst 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.\nEarly 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 ).\nThe 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 ).\nIn 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 ).\nIn 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 ).\nSTC-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 ).\nIt 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.\nDespite 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.\nFrom 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 ).\nIn 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 ).\nDefects 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.\nSTC-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.\nDespite 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.\nThe 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 ).\nUntil 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.\nLow 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 ).\nA 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.\nThe 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 ).\nIn 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.\n\nSTC-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.\nThe 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.\n\nNo new data were generated or analysed in support of this research.","source_license":"public-domain-us","license_restricted":false}