ReviewRegulation of the reproductive cycle and early pregnancy by relaxin family peptides
Introduction
The relaxin family of peptide hormones, whilst structurally related to insulin and the IGFs, appears to have evolved as a separate branch of informational molecules already very early in evolution. Whilst there appear to be no members of the relaxin-like subfamily in insects and worms, several members have been characterized in vertebrates, and particularly in mammals. In deuterostomes, recent discoveries from starfish now suggest that an ancestral relaxin-3-like molecule was already present in this phylum and most importantly was playing a key role in the maturation and release of oocytes (Mita et al., 2009). Significantly, this molecule, called GSS (gonadal stimulating substance), is made within the radial nerves and appears to be performing a role much like the pituitary gonadotropins in other species.
Besides their cladistic similarity, the relaxin-like group of hormones – at least in mammals – is characterized by having receptors which belong to the G-protein coupled receptor (GPCR) family, unlike the insulin branch which all make use of receptor tyrosine kinases. The vertebrate ancestor of the relaxin-like family of peptides, called relaxin-3, is predominantly also a neurohormone, like GSS, and together with the related INSL5 (insulin-like peptide 5), both recognize GPCRs of class A, with small N-terminal extracellular domains (called RXFP3 and RXFP4) (Bathgate et al., 2006). In fish and amphibians, relaxin-3-like molecules are also involved in reproductive processes being highly expressed also in the gonads (Wilson et al., 2009). At some time prior to and concomitant with the emergence of mammals, with their very sophisticated system of viviparity which frees the reproductive process from the arbitrariness of the external environment, the relaxin family of peptide hormones underwent a further radiation. Thus in mammals, particularly in humans, we find altogether seven members of the relaxin hormone family: relaxin-3 and INSL5, predominantly associated with the brain and gut respectively; H1-relaxin, H2-relaxin, INSL3, INSL4 and INSL6, are all associated with reproductive functions specifically linked to viviparity. This has led to the coining of the term ‘neohormone’ for this group of peptide hormones (Anand-Ivell et al., 2013), which serve specifically mammalian physiologies, though others, such as hCG or interferon-tau, are also members. Significantly, H1-relaxin, H2-relaxin and INSL3 make use of different GPCRs (RXFP1 and RXFP2) from those used by relaxin-3 and INSL5 (INSL4 and INSL6 have as yet no known receptors). These GPCRs are affiliated to the class A, rhodopsin-like GPCRs and are distantly related to the receptors for the glycoproteohormones, LH, FSH and TSH, within subclass C of the LGR (leucine-rich repeat-containing GPCR) family (van Hiel et al., 2012). Thus, from an evolutionary and signaling viewpoint, the relaxin family of peptide hormones shares several features with the hormones of the HPG axis, though unlike these have evolved to accommodate additional functions related to viviparity and internal fertilization.
The present review explores the specific roles of relaxin family peptides in female physiology with emphasis on ovarian function, embryo formation and implantation, and early pregnancy up to the end of the first trimester. The role of these peptide hormones in later pregnancy, in lactation and in male reproductive function have been recently covered in other reviews (e.g. Bathgate et al., 2006, Parry and Vodstrcil, 2007, Ivell et al., 2011) and will not be further discussed here.
Section snippets
Relaxin and ovarian function
The term relaxin is used here to refer to the peptide called H2-relaxin in humans, relaxin-1 in rodents, and its homologs, and is thus distinct from the ancestral neurohormone relaxin-3 and its homologs, or from the recently evolved H1-relaxin found in humans and chimpanzees. Relaxin is the major relaxin-like peptide produced within the ovary of most mammalian species, and the hormone which was first extracted and shown to have relaxing-like properties on the term pubic symphysis in guinea-pigs
INSL3 in the ovary during the cycle and early pregnancy
INSL3 (insulin-like peptide 3) is structurally very closely related to relaxin, and for this reason was originally referred to as the relaxin-like factor (RLF; Büllesbach et al., 1999, Ivell, 1997). It was originally identified as a major product of the testicular Leydig cells in the male by independent differential cloning strategies (Adham et al., 1993, Pusch et al., 1996). In the female, it is produced in much lower amounts than in the male, but in the equivalent cells to those in the male,
Other insulin/relaxin-like peptides and female reproduction
Although INSL3 and relaxin are the most studied members of this relaxin-like family of peptides, at least two other members are also thought to be of physiological importance for reproduction, namely INSL4 and INSL6. For neither peptide has a receptor yet been identified, though both have been shown to possess specific functionality.
INSL4 (previously called EPIL or early placental insulin-like) is made in the human placenta and evidently evolved as a paralogue from the relaxin gene with which
Conclusions
Relaxin-like peptides have evolved very much in association with reproductive function, particularly in mammals, where they can be considered as neohormones (Anand-Ivell et al., 2013), and where in both males and females they play key roles in the modulation of reproductive physiology associated with viviparity. In this review, we have highlighted the importance of both relaxin and INSL3 in female reproduction, and drawn attention to substantial gaps in our knowledge of these hormones and of
Acknowledgements
We gratefully acknowledge the Australian Research Council and the National Health and Medical Research Council of Australia, BioInnovation SA, Adelaide, the German Research Council (DFG), and the Leibniz Institute for Farm Animal Biology, Dummerstorf, for generously supporting our research on relaxin family peptides over the last years. We also thank our many collaborators, colleagues and students who have also supported this endeavor with their ideas and hands.
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2018, Encyclopedia of Endocrine DiseasesPairing ultrasonography with endocrinology to elucidate underlying mechanisms of successful pregnancy in the northern fur seal (Callorhinus ursinus)
2018, General and Comparative EndocrinologyCitation Excerpt :Progesterone increases dramatically soon after ovulation and is responsible for differentiation of the endometrium to a secretory phase, and breaks down the transmembrane glycoproteins that act as a physical barrier to embryo attachment in the uterus (Geisert and Bazer, 2015). As gestation progresses and placentation occurs, relaxin concentrations increase and play a role in maintaining the differentiated endometrium, increasing angiogenesis and blood flow, and reducing rates of pregnancy loss (Anand-Ivell and Ivell, 2014). The occurrence of embryonic diapause adds complexity to the otherwise well-characterized sequence of endometrial proliferation/secretion, embryo attachment (i.e., implantation), and maternal recognition of pregnancy in other species (Renfree and Shaw, 2000, 2014).
Comparing human and macaque placental transcriptomes to disentangle preterm birth pathology from gestational age effects
2016, PlacentaCitation Excerpt :KL, or klotho, is under-expressed in pregnancies where the neonate is small-for-gestational-age [50]. INSL6 is a member of the relaxin family of peptide hormones and, although little is known about INSL6 specifically, relaxin expression at the fetomaternal interface has been linked to PPROM pathogenesis and serum relaxin concentration has been identified as a potential PTB biomarker [51,52]. EFNB1 may play a role in cell adhesion and has been shown to be differentially expressed during preeclampsia [53].
Insulin-like peptide 5 is a microbially regulated peptide that promotes hepatic glucose production
2016, Molecular MetabolismCitation Excerpt :Insulin-like peptide (INSL) 5 is a member of the relaxin/insulin family [1], which comprises insulin, insulin-like growth factor (IGF) 1 and 2 [2–4], relaxin 1 and 2, and INSL3-7 [5], and has been recently identified in colonic and brain tissue [1,6–8]. Although other members of the relaxin/insulin family are known to have roles in glucose metabolism, reproductive physiology and remodeling of connective tissue [5,9–12], the function of INSL5 is not clear. One study based on observations in Insl5−/− mice indicated that INSL5 may regulate glucose metabolism by affecting pancreatic beta cell number, but the Insl5−/− phenotype was mild and dependent on the genetic background of the mice [13].