Current Pharmaceutical Design - Volume 18, Issue 3, 2012

The last years have witnessed a tremendous expansion of research areas related on female infertility. Starting from 1978, when Robert Edwards and Patrick Steptoe made possible to obtain live babies by in vitro fertilization (IVF), knowledge of the most intriguing molecular processes occurring in germ and somatic cells of the mammalian ovary is dramatically increased. After 1997, the year of Dolly, the use of oocytes for cloning purposes has opened up exciting and unpredictable scenarios, irreversibly changing our approach to a great number of pathologies. Both IVF and cloning require the utilization of developmentally-competent oocytes, that are produced at the end of a long and complex process occurring in the ovary and strictly influenced by many factors as hormones, nutrition, sexual behavior, exposure to toxicant (e.g. alcohol, smoking and environmental contaminants) [1, 2]. The fact that more than 10% of all couples worldwide are unable to conceive highlights the need of approaching and treating such a sensitive problem in a young and likely healthy population. In recent years, this picture has been further complicated by the significant increase in women postponing pregnancy after 40 years for social reasons [3], and in cancer survivors asking for options to chemotherapy-dependent sterility [4]. The need to respond efficiently to these problems must take into account that a low number of mature oocytes is physiologically produced during whole fertile life (about 500), and that the possibility to produce in vitro high number of fertilizable occytes is still experimental [5]. The reviews presented in this issue of Current Pharmaceutical Design aim at providing the readers with a comprehensive understanding of some “hot” topics in the area of female fertility, from basic to applied research. The first three reviews have dedicated to analyze some of the processes controlling oocyte production. In the first review, De Felici and Farini [6] offered a comprehensive insight of the molecular mechanisms controlling the development of mammalian primordial germ cells, and clarified intriguing aspects of germ cell biology such as the origin of germ cell tumours and the mechanisms allowing the maintenance of totipotency in the germ line. The role played by peptides and regulative factors other than gonadotropins in the intra-ovarian control of oocyte development up to ovulation has been addressed by Canipari, Cellini and myself [7]. Beside molecular pathways, particular emphasis has been devoted to feedback mechanisms operating between oocyte and surrounding somatic cells, and to relationship between absence/anomalous expression of some of these intra-ovarian factors and onset of ovarian cancer. The production of a developmentallycompetent oocyte relies on capacity to store molecules and mRNAs necessary to sustain its own development as well early embryonic stages. Among the thousand genes expressed in the oocyte, a key role is played by maternal effect genes, i.e genes not found in somatic tissues. In their review, Ledda et al. [8] discussed about maternal to embryonic transition in sheep, that is considered a useful model to improve IVF.....

The cell cycle of primordial germ cells (PGCs), the embryonic precursors of gametes, is characterized by a mitotic phase common to both sexes and a mitotic-meiotic switch in the female. In the present work, we will review the results obtained in the last decade by studies aimed to clarify intrinsic and extrinsic regulatory signals of such processes, with particular reference to mouse PGCs. Besides providing a better understanding of how the gamete population is established in mammals, information about the players controlling the PGC cycle will be useful to clarify other intriguing aspects of germ cell biology such as the origin of germ cell tumours and the mechanisms allowing the maintenance of totipotency in the germ line.

The production of a mature oocyte is the major function of the female gonad. This process depends on highly coordinated interplay between all the components of the ovarian follicle, i.e. the oocyte surrounded by epithelial-derived granulosa cells and mesenchymal- derived theca cells. Follicular growth and oocyte maturation are dependent primarily on pituitary-derived gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). However, other bioactive molecules play an important role during this process. In fact, granulosa and theca cells as well as the oocytes are the site of synthesis and/or action of a number of locally-released factors that promote the complex regulation of follicular development. The elucidation of these factors is critical to understand ovarian physiology and pathology.

Assisted reproductive technologies (ART) are successfully applied in several mammals, including humans, thanks to the ability of oocytes and embryos to face maturation, fertilization and first development in vitro. However, efficiency and safety of ART represent main issues. Mammalian oocytes and early embryos are transcriptionally inactive, and rely exclusively on maternal RNAs and proteins, deposited during oocyte growth, until embryonic genome activation (EGA). Such transcriptional quiescence needs complex post-transcriptional and post-translational mechanisms to coordinate meiotic maturation, fertilization, and reprogramming of the nascent genome. These events are the final outcome of complex, hormonally regulated biological processes that translate into specific molecular mechanisms, which are still far from being fully understood. A deep knowledge of these early phases of development is crucial to understand the core mechanisms of life onset, and to optimize the safety and efficiency of in vitro reproductive technologies. This work focuses on meiotic progression and pre-implantation development in mammals, underlining the importance of fundamental molecules stored during oocyte growth and selectively used during early embryogenic stages. Taking into account the species-specific behaviour of these pivotal molecules, this review describes the advantages of using large domestic animals for research in the reproductive field and proposes large domestic animals as models to improve human ART.

Gonadotropin-releasing hormone antagonists (GnRH-ant) are routinely used to prevent premature luteinizing hormone (LH) surges in women undergoing in vitro fertilization (IVF) programs. GnRH-ant act by competitively binding GnRH receptors (GnRHr), leading to rapid pituitary suppression. GnRH-ant can also block extrapituitary GnRHr, including those present in ovary, placenta, and endometrium. A full understanding of the functional roles played by extrapitutary GnRHr, along with a better characterization of the possible reproductive consequences of their blockage may aid the refinement of controlled ovarian stimulation (COS) protocols using GnRHant. This review summarizes current research in the area, especially focusing on the possible impact of GnRH-ant on steroidogenesis, folliculogenesis and endometrial receptivity.

Polycystic ovary syndrome (PCOS) is a complex syndrome of unclear etiopathogenesis characterized by heterogeneity in phenotypic manifestations. The clinical phenotype of PCOS includes reproductive and hormonal aberrations, namely anovulation and hyperandrogenism, which coexist with metabolic disturbances. Reflecting the crosstalk between the reproductive system and metabolic tissues, obesity not only deteriorates the metabolic profile but also aggravates ovulatory dysfunction and hyperandrogenism. Although the pathogenesis of PCOS remains unclear, the syndrome appears to involve environmental and genetic components. Starting from early life and extending throughout lifecycle, environmental insults may affect susceptible women who finally demonstrate the clinical phenotype of PCOS. Diet emerges as the major environmental determinant of PCOS. Overnutrition leading to obesity is widely recognized to have an aggravating impact, while another detrimental dietary factor may be the high content of food in advanced glycated end products (AGEs). Environmental exposure to industrial products, particularly Bisphenol A (BPA), may also exacerbate the clinical course of PCOS. AGEs and BPA may act as endocrine disruptors in the pathogenesis of the syndrome. PCOS appears to mirror the harmful influence of the modern environment on the reproductive and metabolic balance of inherently predisposed individuals.

The human ovary is a complex endocrine gland, which is responsible for production of different hormones and provides mature and competent oocytes for reproduction. Additionally, it produces various substances, such as growth factors and cytokines which are involved in the complex signalling pathways of folliculogenesis or oogenesis. The abnormalities of ovarian function might lead to infertility or manifestation of aggressive cancer. Therefore, stem cells in adult human ovaries are of great interest to reproductive medicine for improved understanding of the mechanisms leading to ovarian infertility or cancer formation, yet they represent a difficult scientific subject, because it is still generally accepted that they do not exist. The persisting dogma is that the end number of follicles is set up at the time of birth, and that there is no neo-folliculogenesis or neo-oogenesis in the postnatal or adult ovaries. The main reason for persistence of the dogma lies in the fact that it is very difficult to perform studies on adult human ovaries; it is impossible to perform in vivo studies, and there is also a lack of ovarian tissue available for research. However, there is more and more evidence about the presence of putative stem cells in postnatal and adult mammalian ovaries. First promising experimental results were obtained in the mouse model, but have been followed also in humans. The aim of this review article is to elucidate the fast upcoming new knowledge of ovarian stem cells, and their potential implications for reproductive medicine and gynecological oncology in the future.

Thanks to the recent advances in cancer care, more and more young women can survive but suffer from infertility as a result of cancer treatment that had to be submitted. There are a variety of methods to preserve fertility, as chemoprotection, ovariopexy, and some assisted reproductive technologies, although some of these are promising but still highly experimental techniques. Cryopreservation of embryos for example is already established, while the oocyte banking is still considered an experimental practice. Many experiments have been conducted around the world on the cryopreservation of ovarian tissue and maturation of ovarian follicles, in an attempt to demonstrate its potential use in fertility preservation. Although in recent years there has been major improvements in the preservation of ovarian tissue, there are still many unresolved technical issues related to these procedures. In this chapter we examine the recent evidence of the pathophysiology of chemotherapy / radiotherapy-induced gonadal toxicity, and recent data regarding the indications and results of the techniques used to preserve fertility in women with cancer.

The female reproductive organs such as ovary, uterus, and placenta are some of the few adult tissues that exhibit regular intervals of rapid growth, and are highly vascularized and have high rates of blood flow. Angiogenesis is a process of vascular growth that is mainly limited to the reproductive system in healthy adult animals. The development of new blood vessels in the ovary and uterus is essential to guarantee the necessary supply of nutrients and hormones. The genetic and molecular mechanisms that control the development of capillary blood vessels in the reproductive organs are beginning to be elucidated. Reproductive organs contain and produce angiogenic factors which may act alone or in concert to regulate the process of vasculature. Vascular endothelial growth factors (VEGFs) and fibroblast growth factor (FGFs) are key factors for vascular system in the reproductive organs. Recent numerous studies reported several roles of VEGFs and FGFs on ovarian and uterine functions. In this review, we focus on the involvement of VEGFs and FGFs as angiogenic factors on reproductive organs and vascular therapy for diseases of reproductive organs using anti-angiogenic agents.

Scientists are able to advance the frontiers of human reproduction by employing a variety of molecular biological techniques to understand the biological processes intricately linked to oocyte and ovarian follicle development. Despite an abundance of knowledge concerning essential pathways which may have critical roles in oogenesis and folliculogenesis, the repertoire of medications to treat female fertility problems remains limited to a few classes of drugs involved in the induction or suppression of folliculogenesis and ovulation; many of which are not specific in their drug actions and can give rise to complications during clinical application. This paper aims to review biomolecules and pathways (e.g. PI3K, WNT, MAPK) pertinent to ovarian follicular development and active in human oocytes, including those involved in communication between somatic cells within the ovary (cumulus cells, granulosa cells and thecal cells) and the oocyte itself. These biomolecules which are involved in the nuclear and cytoplasmic maturation of oocytes and the control of ovarian folliculogenesis have potential as targets for improved ovarian stimulation, optimisation of oocyte maturation, and as biomarkers of oocyte viability assessment.

RNA interference, a recently discovered new mechanism controlling gene expression via small RNAs, was shown to be involved in the characterization and control of basic ovarian cell functions. The main classes of small RNAs, as well as their expression in ovaries have been described. Furthermore, the successful application of RNA interference for the study and control of basic ovarian functions (fertility, proliferation, apoptosis, secretory activity, luteogenesis, oocyte maturation and related ovarian cell malignant transformation) and production of recombinant proteins has been demonstrated. Application of RNA interference in reproductive biology and medicine can be successful in three main areas - (1) characterization and prediction of physiological and pathological state (association between particular small RNA and physiological or pathological processes), (2) application of small RNAs for regulation of reproductive processes and (3) treatment of reproductive disorders or their particular indexes. Problems of improvement of small RNA delivery to target ovarian cells and potent RNA interference-related approaches for the treatment of ovarian disorders (especially of ovarian cancer) have been discussed.