Activins in reproductive biology and beyond

Abstract

Background: Activins are members of the pleiotrophic family of the transforming growth factor-beta (TGF-β) 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 β subunits, act via a classical TGF-β 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.

Keywords: activin; cancer; follistatin; inflammation; inhibin; ovary; placenta; pre-eclampsia; pregnancy; testis.