BACKGROUND: Activins are members of the pleiotrophic family of the transforming growth factor-beta (TGF-beta) superfamily of cytokines, initially isolated for their capacity to induce the release of FSH from pituitary extracts. Subsequent research has demonstrated that activins are involved in multiple biological functions including the control of inflammation, fibrosis, developmental biology and tumourigenesis. This review summarizes the current knowledge on the roles of activin in reproductive and developmental biology. It also discusses interesting advances in the field of modulating the bioactivity of activins as a therapeutic target, which would undoubtedly be beneficial for patients with reproductive pathology. METHODS: A comprehensive literature search was carried out using PUBMED and Google Scholar databases to identify studies in the English language which have contributed to the advancement of the field of activin biology, since its initial isolation in 1987 until July 2015. 'Activin', 'testis', 'ovary', 'embryonic development' and 'therapeutic targets' were used as the keywords in combination with other search phrases relevant to the topic of activin biology. RESULTS: Activins, which are dimers of inhibin beta subunits, act via a classical TGF-beta signalling pathway. The bioactivity of activin is regulated by two endogenous inhibitors, inhibin and follistatin. Activin is a major regulator of testicular and ovarian development. In the ovary, activin A promotes oocyte maturation and regulates granulosa cell steroidogenesis. It is also essential in endometrial repair following menstruation, decidualization and maintaining pregnancy. Dysregulation of the activin-follistatin-inhibin system leads to disorders of female reproduction and pregnancy, including polycystic ovary syndrome, ectopic pregnancy, miscarriage, fetal growth restriction, gestational diabetes, pre-eclampsia and pre-term birth. Moreover, a rise in serum activin A, accompanied by elevated FSH, is characteristic of female reproductive aging. In the male, activin A is an autocrine and paracrine modulator of germ cell development and Sertoli cell proliferation. Disruption of normal activin signalling is characteristic of many tumours affecting reproductive organs, including endometrial carcinoma, cervical cancer, testicular and ovarian cancer as well as prostate cancer. While activin A and B aid the progression of many tumours of the reproductive organs, activin C acts as a tumour suppressor. Activins are important in embryonic induction, morphogenesis of branched glandular organs, development of limbs and nervous system, craniofacial and dental development and morphogenesis of the Wolffian duct. CONCLUSIONS: The field of activin biology has advanced considerably since its initial discovery as an FSH stimulating agent. Now, activin is well known as a growth factor and cytokine that regulates many aspects of reproductive biology, developmental biology and also inflammation and immunological mechanisms. Current research provides evidence for novel roles of activins in maintaining the structure and function of reproductive and other organ systems. The fact that activin A is elevated both locally as well as systemically in major disorders of the reproductive system makes it an important biomarker. Given the established role of activin A as a pro-inflammatory and pro-fibrotic agent, studies of its involvement in disorders of reproduction resulting from these processes should be examined. Follistatin, as a key regulator of the biological actions of activin, should be evaluated as a therapeutic agent in conditions where activin A overexpression is established as a contributing factor.
Microphysiologic systems (MPS), including new organ-on-a-chip technologies, recapitulate tissue microenvironments by employing specially designed tissue or cell culturing techniques and microfluidic flow. Such systems are designed to incorporate physiologic factors that conventional 2D or even 3D systems cannot, such as the multicellular dynamics of a tissue–tissue interface or physical forces like fluid sheer stress. The female reproductive system is a series of interconnected organs that are necessary to produce eggs, support embryo development and female health, and impact the functioning of non-reproductive tissues throughout the body. Despite its importance, the human reproductive tract has received less attention than other organ systems, such as the liver and kidney, in terms of modeling with MPS. In this review, we discuss current gaps in the field and areas for technological advancement through the application of MPS. We explore current MPS research in female reproductive biology, including fertilization, pregnancy, and female reproductive tract diseases, with a focus on their clinical applications. Impact statement This review discusses existing microphysiologic systems technology that may be applied to study of the female reproductive tract, and those currently in development to specifically investigate gametes, fertilization, embryo development, pregnancy, and diseases of the female reproductive tract. We focus on the clinical applicability of these new technologies in fields such as assisted reproductive technologies, drug testing, disease diagnostics, and personalized medicine.
Kisspeptins, a family of neuropeptides encoded by the Kiss1 gene that are mainly expressed in discrete neuronal populations of the hypothalamus, have recently emerged as essential upstream regulatory elements of GnRH (gonadotropin-releasing hormone) neurons and, thereby, potent elicitors of gonadotropin secretion. Indeed, kisspeptins are now recognized as important regulators of key aspects of the maturation and function of the reproductive axis, including the sexual differentiation of the brain, the timing of puberty, the adult regulation of gonadotropin secretion by gonadal hormones, and the control of fertility by metabolic and environmental (e.g., photoperiod) cues. Appreciation of these fundamental biological features has led to the contention that kisspeptins are indispensable elements of the reproductive brain whose relevance goes beyond their crucial physiological roles and may pose potential pathophysiological and therapeutic interest. In spite of such a consensus, recent developments in the field have helped to expand, and somewhat challenged, our current understanding of the neuroendocrine and molecular mechanisms whereby some of the effects of kisspeptins are conducted. This review aims to provide a synoptic and balanced account of the consensus knowledge and recent findings in the field of kisspeptin physiology, which we predict will be crucial in shaping the progress of our understanding of the roles played by this family of neuropeptides in reproductive biology.
The light/dark cycle and suprachiasmatic nucleus rhythmicity are known to have important influences on reproductive function of rodents. We studied reproductive function in female heterozygous and homozygous brain and muscle ARNT-like protein 1 ( Bmal1 , also known as Arntl ) null mice, which lack central and peripheral cellular rhythms. Heterozygous Bmal1 mice developed normally and were fertile, with apparent normal pregnancy progression and litter size, although postnatal mortality up to weaning was high (1.1–1.3/litter). The genotype distribution was skewed with both heterozygous and null genotypes underrepresented (1.0:1.7:0.7; P <0.05), suggesting loss of a single Bmal1 allele may impact on postnatal survival. Homozygous Bmal1 null mice were 30% lighter at weaning, and while they grew at a similar rate to the wild-type mice, they never achieved a comparable body weight. They had delayed vaginal opening (4 days), disrupted estrus cyclicity, and reduced ovarian weight (30%). Bmal1 null mice had a 40% reduction in ductal length and a 43% reduction in ductal branches in the mammary gland. Surprisingly, the Bmal1 mice ovulated, but progesterone synthesis was reduced in conjunction with altered corpora lutea formation. Pregnancy failed prior to implantation presumably due to poor embryo development. While Bmal1 null ovaries responded to pregnant mare serum gonadotropin/human chorionic gonadotropin stimulation, ovulation rate was reduced, and the fertilized oocytes progressed poorly to blastocysts and failed to implant. The loss of Bmal1 gene expression resulted in a loss of rhythmicity of many genes in the ovary and downregulation of Star . In conclusion, it is clear that the profound infertility of Bmal1 null mice is multifactorial.
Spermatozoa were the first cell type in which the cellular generation of reactive oxygen was demonstrated. This activity has now been confirmed in spermatozoa from all mammalian species examined including the rat, mouse, rabbit, horse, bull and human being. Under physiological circumstances, cellular redox activity is thought to drive the cAMP-mediated, tyrosine phosphorylation events associated with sperm capacitation. In addition to this biological role, human spermatozoa also appear to suffer from oxidative stress, with impacts on the normality of their function and the integrity of their nuclear and mitochondrial DNA. Recent studies have helped to clarify the molecular basis for the intense redox activity observed in defective human spermatozoa, the nature of the subcellular structures responsible for this activity and possible mechanisms by which oxidative stress impacts on these cells. Given the importance of oxidative damage in the male germ line to the origins of male infertility, early pregnancy loss and childhood disease, this area of sperm biochemistry deserves attention from all those interested in improved methods for the diagnosis, management and prevention of male-mediated reproductive failure.
The relaxin-like factor (RLF), which is the product of the insulin-like factor 3 (INSL3) gene, is a new circulating peptide hormone of the relaxin-insulin family. In male mammals, it is a major secretory product of the testicular Leydig cells, where it appears to be expressed constitutively but in a differentiation-dependent manner. In the adult testis, RLF expression is a good marker for fully differentiated adult-type Leydig cells, but it is only weakly expressed in prepubertal immature Leydig cells or in Leydig cells that have become hypertrophic or transformed. It is also an important product of the fetal Leydig cell population, where it has been demonstrated using knockout mice to be responsible for the second phase of testicular descent acting on the gubernaculum. INSL3 knockout mice are cryptorchid, and in estrogen-induced cryptorchidism, RLF levels in the testis are significantly reduced. RLF is also made in female tissues, particularly in the follicular theca cells of small antral follicles and in the corpus luteum of the cycle and pregnancy. The ruminant ovary has a very high level of RLF expression, and analysis of primary cultures of ovarian theca-lutein cells indicated that, as in the testis, expression is probably constitutive but differentiation dependent. Female INSL3 knockout mice have altered estrous cycles, where RLF may be involved in follicle selection, an idea strongly supported by observations on bovine secondary follicles. Recently, a novel 7-transmembrane domain receptor (LGR8 or Great) has been tentatively identified as the RLF receptor, and its deletion in mice leads also to cryptorchidism.