Review
Regulation of the reproductive cycle and early pregnancy by relaxin family peptides

https://doi.org/10.1016/j.mce.2013.08.010Get rights and content

Highlights

  • The relaxin peptide hormone family is involved in ovarian and uterine function.

  • Relaxin is concerned with follicle growth, ovulation, implantation and placental establishment.

  • INSL3 is a key player in intrafollicular androgen production and regulation.

  • Fetal INSL3 can impact on placental and maternal physiology.

  • INSL4, INSL5 and INSL6 may also be involved in female reproduction.

Abstract

The relaxin family of peptide hormones are structurally closely related to one another sharing a heterodimeric A–B structure, like that of insulin. They may also be active as unprocessed B–C–A pro-forms. Relaxin has been shown to pay a key role within the ovary, being involved in follicle growth, and ovulation. Relaxin is produced in large amounts also by the corpus luteum where it acts as an endocrine hormone positively affecting implantation, placentation and vascularization during the all-important first trimester phase of pregnancy establishment. Relaxin exerts its functions via the receptor RXFP1. Insulin-like peptide 3 (INSL3) in contrast acts through the related receptor RXFP2, and plays an essential role in the production of androgens within growing antral follicles. INSL3 is also produced in large amounts by the male fetus shortly after sex determination, where it controls the first transabdominal phase of testicular descent. However, this fetal INSL3 is also able to influence placental and maternal physiology, indicating associations with later preeclampsia and/or fetal growth restriction. Other members of this relaxin-like family of peptides, such as INSL4, INSL5 and INSL6 are less well studied, though all suggest modulatory roles in ovarian and/or placental function.

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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