Regulators of Ovarian Functions [1 ed.] 9781613244685, 9781629485744

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OBSTETRICS AND GYNECOLOGY ADVANCES

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REGULATORS OF OVARIAN FUNCTIONS

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REGULATORS OF OVARIAN FUNCTIONS

ALEXANDER V. SIROTKIN, PH.D.

New York

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Copyright © 2014 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com

NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‟ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data Regulators of ovarian functions / Alexander V. Sirotkin. xv, 194 p. : ill. ; 24 cm. Includes bibliographical references and index.

ISBN:  (eBook) 1. Ovaries --Molecular aspects. 2. Ovulation --Regulation. 3. Ovary --physiology. 4. Menstrual Cycle -physiology. 5. Transcription Factors --physiology. I. Sirotkin, Alexander V. QP261 .S57 2011 612.6/2 2010003164

Published by Nova Science Publishers, Inc. † New York

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Contents

Preface

ix

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Introduction

xiii

Chapter 1

The Ovary and Ovarian Cycle 1.1. The Ovary References

1 1 11

Chapter 2

Oocytes and their Maturation 2.1. Oocyte 2.2. Oocyte Nuclear Maturation 2.3. Oocyte Cytoplasmic Maturation References

15 15 16 20 22

Chapter 3

Extracellular Regulators of Ovarian Functions 3.1. Function and Classification of Biological Signaling Substances 3.2. Hormones and Hormone-Like Substances 3.3. Extracellular Regulators of Ovarian Functions References

25

Protein Kinases in Control of Ovarian Functions 4.1. Introduction 4.2. Function and Classification of Protein Kinases 4.3. Presence of Protein Kinases in the Ovary 4.4. Protein Kinases Control Ovarian Cell Proliferation

75 75 76 77

Chapter 4

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26 27 31 63

79

vi

Alexander V. Sirotkin 4.5. Protein Kinases Control Ovarian Cell Apoptosis 4.6. Protein Kinases Control Maturation of OocyteCumulus Complex 4.7. Protein Kinases Control Release of Hormones by Ovarian Cells 4.8. Protein Kinases Control Hormone Receptors and Response to Hormones 4.9. Protein Kinases Mediate Effect of Hormones on the Ovary 4.10. Interrelationships between Different Protein Kinases in the Ovary 4.11. Protein Kinases can be used for Control of Fertility, Ovarian Cycle and Health References

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Chapter 5

Transcription Factors in Control of Ovarian Functions 5.1. Function and Classification of Transcription Factors 5.2. Transcription Factors Involved in Control of Follicular Development And Selection 5.3. Transcription Factors Involved in Control of Ovarian Cell Proliferation And Cancerogenesis 5.4. Transcription Factors Involved in Control of Ovarian Cell Apoptosis 5.5. Transcription Factors Involved in Control of Ovarian Secretory Activity 5.6. Transcription Factors Involved in Oocyte/Cumulus Maturation 5.7. Transcription Factors Involved In Control of Ovulation And Luteogenesis 5.8. Transcription Factors Involved in Mediation Effect of Hormones 5.9. Transcription Factors Involved in Mediation Effect of Growth Factors an Cytokines 5.10. Conclusion References

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82 82 84 86 87 88 90 93 101 101 103 105 107 107 112 113 114 115 116 118

Contents Chapter 6

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Chapter 7

Chapter 8

vii

RNA Interference in Control of Ovarian Functions 6.1. Function and Classification of Small RNAs 6.2. Expression of Small RNAs in the Ovary 6.3. RNA Interference and Ovarian Cell Proliferation 6.4. RNA Interference and Ovarian Cell Apoptosis 6.5. RNA Interference and Ovarian Secretory Activity 6.6. RNA Interference and Ovarian Luteogenesis 6.7. RNA Interference and Oocyte Maturation 6.8. RNA Interference and Recombinant Protein Production 6.9. Improvement of Small RNA Delivery References

125 126 128

Regulation of Oocyte Maturation 7.1. Extracellular Regulators of Oocyte Nuclear and Cytoplasmic Maturation 7.2. Intracellular Regulators Of Oocyte Nuclear Maturation 7.3. Intracellular Regulators of Oocyte Cytoplasmic Maturation 7.4. Interrelationships between Regulators of Oocyte Maturation References

153

Physiological and Artifical Regulation of Ovarian Cycle 8.1. Physiological Regulation of Ovarian Cycle 8.2. Artificial Regulation of the Ovarian Cycle References

Index

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129 133 135 141 141 142 143 144

153 155 158 159 160 163 163 175 180 185

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Preface Reproduction is a key biological process in existence of species, an important subject of human and veterinary medicine, animal science and biotechnology, assisted reproduction and other disciplines. Furthermore, it is the most complicated process from the viewpoint of number of involved processes, regulators and their interrelationships. I am happy to remember the old good times of my studentship, where regulation of reproduction looked very simple, clear and attractive. Everybody was sure, that, besides external factors (feeding, mate etc.) reproduction is regulated by four kinds of hormones – gonadotropin-releasing hormone, gonadotropins, and steroid hormones and sometimes with prostaglandins. Peptide hormones affected target cells and their genes through specific membrane receptors and cAMP, and steroids – through cytoplasm receptors, and these substances were enough to explain and to control reproductive processes and related events and disorders. At present the available information concerning regulation of reproductive processes have been dramatically multiplied. A hundreds and thousands of new substances appear to exist and to be involved in control of reproductive processes at different regulatory levels. From one side, they provide a tool with potentially unlimited capacity to characterize, to predict and to control reproductive processes and to treat reproduction associated disorders including currently growing infertility and most ubiquitous, reproduction-associated, cancer. From the other side, paradoxically, usage of this tool is sometimes complicated by huge amount of available data. Some these data, being correct, are contradictory due to different models and methodological approaches used for their collection. All available data concern particular substance and process are limited because nobody now is able to describe and even to imagine real

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Alexander V. Sirotkin

complex interrelationships between different regulators of reproduction. Nevertheless, existence and progress in disciplines related to reproduction listed above require understanding or at least systematization and generalization of the available relevant knowledge. Some molecules involved in control of reproduction discovered a long time ago (for example, some hormones) are already described in a number of overviews. Some kind of recently discovered hormones, growth factors are described only in a limited number of publications. Finally, there are practically no reviews concerning the role of so important regulatory molecules as protein kinases, transcription factors and small RNAs in control of reproduction. The present book is written at the basis of available publications, several our previous reviews (Sirotkin et al., 2003, 2010; Sirotkin, 2005, 2010a,b,c; Sirotkin and Luck, 2008) and our research experience in this area. This book represents an attempt to review the recent knowledge concerning basic processes occurring in the most important female reproductive organ – ovary and their regulators. The most important processes (ovarian cyclic changes and oogenesis), as well as their extracellular (hormones and growth factors) and intracellular (protein kinases, transcription factors, small RNAs) regulators are described. Data concerning processes or substances well described in previous reviews are summarized here in a short form with references to corresponding reviews. Intracellular substances not reviewed previously (protein kinases, transcription factors, small RNAs) are described more detailed. In short description of each signaling substance we have try to summarize available data concerning its involvement in control of basic processes (proliferation, apoptosis, ovarian cycle, oogenesis) within the ovary and their possible practical application. Two chapters illustrate complex interrelationships between single regulators in control of the most important and complex reproductive events - oocyte maturation and ovarian cycle. This book is not intended to be a comprehensive review of all regulatory substances involved in ovarian functions, but aims to provide an introductory framework for understanding the most significant signaling molecules and processes within the ovary to be affected by these molecules. To simplify understanding the control of each event, we listed its possible regulators at the levels of extracellular substances, protein kinases, transcription factors, small RNAs etc., but we did not follow single whole particular signaling pathways (for example, whole signaling cascade including particular hormone, its receptor, post-receptor cyclic nucleotides, protein kinases, transcription factors a.o.). To simplify search for literary sources, each chapter contains is own list of references.

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Preface

xi

I believe, this book can help the students and research scientists working in areas of biology of reproduction, medicine, biotechnology and assisted reproduction, whose would like to know the current state of knowledge concerning regulator of ovarian functions, as well as looking for new ideas and approaches in this promising and interesting topics. Alexander V. Sirotkin Animal Production Research Centre and Constantine the Philosopher University, Nitra, Slovakia E-mail: [email protected]

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References [1] Sirotkin AV, Makarevich AV, Grossmann R, Kotwica J, Schaeffer H-J, Marnet P-G, Kwon H, Sanislo P, Florkovicova I, Petrak J, Rafal J, Pivko J, Hetenyi L. Regulators of ovarian function. In: Regulation and Evaluation of Ovarian Function and Embryogenesis in Normal and Transgenic Animals in vitro and in vivo“(M.R. Luck ed.). Research Institute of Animal Production, Nitra, Slovakia, 2003, pp. 9-25. [2] Sirotkin AV. Control of reproductive processes by growth hormone: extraand intracellular mechanisms. Vet J. 2005 170:307-317. [3] Sirotkin AV, Luck M. The ovarian cycle, oogenesis and their regulation. In: Animal Biotechnology (J. Laurinčik ed.), Constantine the Philosopher University in Nitra, Prírodovedec, Nitra, SR, 2008, pp. 10-28. [4] Sirotkin AV., Makarevich AV, Grossmann R. Protein kinases and ovarian functions. J Cell Physiol. 2010 226:37-45. [5] Sirotkin AV. Protein kinases: signaling molecules controlling ovarian functions. The Int J Biochemistry & Cell Biol 2010a 42:1927-1930. [6] Sirotkin AV. RNA interference and ovarian functions. J Cell Physiol. 2010b 225:345-363. [7] Sirotkin AV. Transcription factors and ovarian functions J Cell Physiol. 2010c 225:20-26.

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Introduction This book represents an attempt to review the most recent knowledge concerning basic processes occurring in the most important female reproductive organ – ovary and their regulators. The most important processes (ovarian cyclic changes and oogenesis), as well as their extracellular (hormones and growth factors) and intracellular (protein kinases, transcription factors, small RNAs) regulators are described. Data concerning processes or substances well described in previous reviews are summarized here in a short form with references to corresponding reviews. Chapter 1 - This chapter provides basic knowledge concerning ovarian structures, their development and cyclic changes. Folliculogenesis includes stages of primordial, primary preantral, antral and preovulatory (Graafian) follicle. At each stage of follicullogenesis follicles undergo selection due to survival and development of selected follicles and atresia/death of the rest. The equilibration between these two processes determines fecundity. Ovulation includes a number of intraovarian events including meiosis reinitiation in oocyte, expansion and mucification of surrounding cumulus oophorus due to accumulation of hyaluronic acid, digestion of follicular wall with proteolytic and collagenolytic enzymes, as well as with its luteinisation associated with changes in follicle cell morphology, vascularisation and secretory activity and in formation of corpus luteum. If the oocyte is not fertilized and embryo implantation does not occur, the corpus luteum degenerates. These cyclic changes and their visible expression represent ovarian and estrous cycles. Chapter 2 - This chapter reviews the basic processes related to nuclear maturation (meiosis) and cytoplasmic maturation of oocytes. Chapter 3 - This chapter reviews the most known extracellular regulators of ovarian functions. First sub-chapters shortly outline classification,

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Alexander V. Sirotkin

nomenclature and interrelationships between of biological signaling substances including hormones and hormone-like substances. Next subchapters represent short description of the following extracellular regulators of ovarian functions: gonadotropin-releasing hormone (GnRH), gonadotropins FSH and LH, steroid hormones progestins, androgens and estrogens, growth hormone (GH), prolactin, oxytocin and its analogues, leptin, ghrelin, obestatin, prostaglandins, indoleamines serotonin and melatonin, insulin-like growth factors (IGFs), epidermal growth factors (EGFs), vascular endothelial growth factor (VEGF), thrombopoietin (TPO), erytropoietin (EPO), hepatocyte growth factor (HGF), growth factors of Hedgehog, Wnt, and Notch families, cytokines colony stimulating factors (CSFs), tumor necrosis factors (TNFs), interleukines (ILs), inhibin, activin, follistatin, anti-Mullerian hormone (AMH), bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). Basic information concerning expression of these molecules and their receptors in the ovary, their action on ovarian cell proliferation, apoptosis, ovarian follicle growth and development, secretory activity, possible practical application of these substances and references to key related publications are provided. Chapter 4 - Present review of available literature suggests, that ovarian cells produce a number of PKs, whose expression depends on type of cells, their state and action of hormones and other PKs. A number of PKs are involved in control of ovarian cell proliferation, apoptosis, oocyte maturation, hormone release, reception and response to hormones, as well as in mediating action of hormones on these ovarian functions. Complexity of interrelationships between different PK-dependent signaling pathways occurs. PKs and their regulators could be used for characterization, prediction and control of ovarian folliculogenesis and atresia, corpus luteum functions, oocyte maturation, fertility, release of hormones, response of ovarian structures to hormonal regulators, as well as for treatment of some reproductive disorders. Chapter 5 - This chapter represents a review of contemporarily knowledge concerning involvement of transcription factors in control of different ovarian functions. After introduction of basic functions and classification of transcription factors, the available data concerning involvement of transcription factors in control of the following ovarian events are present: follicular development and selection, ovarian cell proliferation and cancerogenesis, ovarian cell apoptosis, ovarian secretory activity, oocyte/cumulus maturation, ovulation and luteogenesis, mediation effect of hormones, growth factors and cytokines. The importance of transcription factors of Smad family, of forkhead transcription factor (Fox) family, of breast

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Introduction

xv

cancer associated genes/transcription factor, hypoxia-induced transcription factors (HIFs) and of other transcription factors in control of these processes has been demonstrated. Chapter 6 - RNA interference, a recently discovered new mechanism controlling gene expression via small RNAs, was shown to be involved in 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 study and control of basic ovarian functions (proliferation, apoptosis, secretory activity, luteogenesis, oocyte maturation and related ovarian cell malignant transformation) and production of recombinant proteins have been demonstrated. Application of RNA interference in reproductive biology and medicine can be successful in two 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 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 treatment of ovarian disorders (especially of ovarian cancer) have been discussed. Chapter 7 - This chapter represents a short overview of extra- and intracellular regulators of oocyte nuclear and cytoplasmic maturation. These processes are regulated by a number of extracellular regulators (hormones, growth factors, connexins, meiosis activating sterols) and intracellular signaling molecules (meiosis promoting factor MPF, mitogen activated protein kinase MAPK, cAMP/protein kinase A, protein kinase B/Akt, Janus kinases, Aurora A kinases, calcium ions, oocyte maturation inhibitor OMI, glycosaminoglycans a.o.), whose can interrelate and form signalling cascade regulating maturation of oocyte-cumulus oophorus complex. Chapter 8 - This chapter describes the role of particular, mainly extracellular, physiological regulators (hormones, growth factor, cytokines etc.) and their complex interrelationships in control of ovarian cycle (formation of primordial follicles and early oogenesis, development of primary and secondary/antral follicles, pre-ovulatory changes, ovulation, luteogenesis and luteolysis). Additional sub-chapter provides a short description of approaches currently used for artifical regulation of ovarian cycle (synchronization of the ovarian cycle, contraception, as well as induction of ovulation and superovulation).

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Chapter 1

The Ovary and Ovarian Cycle

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Abstract This chapter provides basic knowledge concerning ovarian structures, their development and cyclic changes. Folliculogenesis includes stages of primordial, primary preantral, antral and preovulatory (Graafian) follicle. At each stage of follicullogenesis follicles undergo selection due to survival and development of selected follicles and atresia/death of the rest. The equilibration between these two processes determines fecundity. Ovulation includes a number of intraovarian events including meiosis reinitiation in oocyte, expansion and mucification of surrounding cumulus oophorus due to accumulation of hyaluronic acid, digestion of follicular wall with proteolytic and collagenolytic enzymes, as well as with its luteinisation associated with changes in follicle cell morphology, vascularisation and secretory activity and in formation of corpus luteum. If the oocyte is not fertilized and embryo implantation does not occur, the corpus luteum degenerates. These cyclic changes and their visible expression represent ovarian and estrous cycles.

1.1. The Ovary The ovary is the central organ of the female reproductive system. It has two main functions: the production of gametes (oocytes) and the secretion of signaling and regulatory substances. The secretions of the ovary influence

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other parts of the reproductive system, including those which control female maturation, cyclicity, gamete production and behavior (brain, pituitary gland, the ovary itself), and those which support embryo development, gestation and lactation (reproductive tract, uterus, mammary gland). The ovary has two structural regions: the outer cortex contains follicles at various stages of development together with structures derived from follicles, whilst the inner medullar consists mainly of stromal tissues and vascular elements (Fig. 1). Ovarian structures and their cyclic changes are described in special reviews (Gougeon, 2004; Aerts and Bols, 2008a,b; Oktem and Oktay, 2008; Peter et al., 2009), and they are illustrated by Fig.1-4.

Figure 1. Ovarian structures and their development from primary follicle up to corpus luteum. (http://www.uoguelph.ca/502.html).

1.1.1. Folliculogenesis The principal functional unit of the ovary is the follicle, which go through several stages if development (Fig.1) before preovulatory stage (Fig.2) or death. Primordial germ cells (precursors of oocytes) appear within the embryonic ovary and multiply by mitosis during prenatal ontogenesis. During postnatal ontogenesis, several thousands of germ cells cease their mitosis and begin meiosis (see below), becoming oogonia and then oocytes. Neighboring

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ovarian cells differentiate into follicular somatic cells, under the influence of oogonia/oocyte-derived factors (Oktem and Oktay, 2008; Tingen et al., 2009).

Figure 2. Terms and concepts related to follicular wave emergence (WE) and subsequent development of Wave 1 (anovulatory) and Wave 2 (ovulatory, OV) in association with respective FSH surges during the bovine estrous cycle. (from Peter et al., 2008).

Each oocyte becomes enclosed by one layer of flat follicular cells to form a primordial follicle. Subsequent proliferation of follicular cells leads to the formation of a primary follicle surrounded by several layers of cuboidal, epithelial cells. Under the influence of the oocyte, which is now in a state of meiotic arrest, the cells differentiate and produce a membrane made of protein and glycoprotein called the zona pellucida; they also supply the oocyte with nutrients and secrete signaling substances, including hormones such as estrogen, which regulate oogenesis and other components of the reproductive system. On the other hand, oocyte through oocyte-specific secretes (see below), promotes development of surrounding follicle (Fortune, 2003; Craig at al., 2007; Hutt and Albertini, 2007; Mermillod, 2008; McLaughlin and McIver, 2009) The single layer of cells immediately adjacent to the oocyte, the corona radiata, have long processes which penetrate the zona pellucida and connect with the oocyte by gap junctions. The layers of more elongated cells

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surrounding these are called granulosa cells (and form the zona granulosa or stratum granulosum) and they initially fill the space between the corona cells and the outer basement membrane (basal lamina or membrana basalis) of the follicle. The outermost (mural) layer of granulosa cells are columnar rather than cuboidal and have intimate contact with the extracellular matrix components which make up the membrane (including collagen Type IV, laminin and heparan sulfate proteoglycan). The basement membrane is synthesized by the granulosa cells, working in cooperation with cells on its outer side which make up the theca interna. The theca interna is comprised of several different types of cell including fibroblasts, capillary endothelial cells and endocrine cells. The latter secrete a range of steroid and protein hormones, some of which may be transported across the basement membrane to regulate the activity of the granulosa cells and the oocyte and to be converted into other hormones. For example, in many species thecal androgen is converted by granulosa cells into estrogens which is then carried into the general circulation. A further external layer of tissue, the theca externa, consists of structural cells, connective tissue and capillaries. The latter supply the whole follicle with nutrients, gases and extra-ovarian signaling molecules. They reach into the theca interna but do not penetrate the follicular basement membrane. This means that the internal parts of the follicle (granulosa, corona, oocyte) are avascular and must receive blood-born nutrients, gases and other substances by transfer across the follicle wall (Gougeon, 2004). During early follicular growth, granulosa cells divide and fill the expanding follicle. At a certain stage of growth, the volume of the follicle increases more rapidly than the total volume of the proliferating granulosa cells. Some inner layers of cells may also die or fail to replicate, possibly because of limited nutrient availability. At this stage, the differential volume of the expanding follicle fills with a fluid (follicular fluid or liquor folliculi) and a chamber or antrum is formed which largely separates the outer granulosa cell layers from the oocyte and corona. Some granulosa cells may remain contiguous with the corona cells, forming a short stalk called the cumulus oophorus. Follicles reaching this stage of development are called secondary or antral follicles (Gougeon, 2004; Aerts and Bols, 2008a; Oktem and Oktay, 2008). The follicular fluid of an antral follicle is essentially a transudate of serum, derived from the thecal capillaries. It is partially filtered during its passage across the capillary endothelium, through the theca and across the follicle wall, and it is further modified by secretions from the granulosa cells and oocyte. It

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therefore contains small to medium sized serum factors, supplemented with relatively high concentrations of ovarian hormones and other follicle-derived products. The granulosa cells produce proteoglycans which swell up with water to form very large molecules; these are in particularly high abundance in follicular fluid. At each stage of folliculogenesis, from the primordial and primary stages and through each level of antral growth, there is an intensive selection and loss of follicles. As a result, more than 99% of the primordial follicles originally present in the ovary are subjected to degeneration (known as atresia) due to programmed cell death (apoptosis). Final desteny of follicle depends of balance between apoptosis and proliferation rate in follicular cells (Craig et al., 2007; Webb and Campbell, 2007; Adams et al., 2008). Those that survive selection have the potential to ovulate, depending on stage of the ovarian cycle at which they mature and the reproductive characteristics of the species, breeds or individuals. Ovarian transplant studies in both cattle and sheep demonstrated that it takes approximately 4 months for primordial follicles to reach dominance (Webb and Campbell, 2007). Number of primordial follicles initiating growth (Fortune, 2003; Skinner, 2005) and number of follicles continuing growing and subjected to subsequent follicular atresia and selection (Hunter, 2004; Craig et al., 2007) are the most important factors determining number of matured and ovulated eggs and fecundity. In growing follicles, only a subset of oocytes are capable to maturation, fertilization and early embryo development. This proportion of competent oocytes is increasing along with size of oocyte and follicle and decreasing along with occurrence of follicular atresia/apoptosis (Feng et al., 2007; Miyano and Manabe, 2007; Mermillod et al., 2008). In one ovarian cycle one distinguish from one to four (mainly two or three) so called follicular waves, during whose particular cohort of follicles are entrained to recruitment, rapid growth and atresia (Adams et al., 2008; Mihm and Evans, 2008; Peter et al., 2009). (Fig.2). In the end of the least follicular wave only one or several large, fully differentiated dominant antral follicle reaching the preovulatory stage of development is called a Graafian follicle (Fig. 3). Perhaps a curious feature of ovarian science is that almost nothing is known about the tissue processes by which follicle growth occurs. This is despite our extensive knowledge of how this and other aspects of folliculogenesis are controlled by hormones and local factors (described below).

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Figure 3. Structure of mature (Graafian) follicle http://upload.wikimedia.org/wikipedia/ n/5/50/Mature_Graffian_follicle.jpg).

It is unknown, for example, whether follicles grow as a cellular response to the pressure of fluid accumulating in the antrum, or whether fluid enters passively to fill the expanding volume. The former possibility seems the more likely, but it in turn raises the question of what causes the fluid to accumulate. We also need to understand what controls the movement of fluid from the blood as it passes across the capillary endothelium, through the theca and across the follicle wall. The basement membrane of the wall ultimately determines the integrity of the follicle prior to ovulation. This extremely fine structure, separating the theca and granulosa layers, grows rapidly as a sphere, without elastic stretching or change in thickness: there must be remarkable coordination between the granulosa and theca cells so that its collagen, laminin and proteoglycan constituents can be continuously deposited and remodeled without loss of integrity (Irving-Rodgers and Rodgers, 2006). Formation and transition of primordial follicle to the primary follicle and their further development directly affect the number of oocytes available to a

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female throughout her reproductive life. At birth, the ovary contains a finite number of primordial follicles with oocytes ("the ovarian reserve", Broekmans et al., 2006; Roudebush et al., 2008). As the ovary ages, the ovarian reserve will decline. Once the pool of primordial follicles is depleted, a natural menopause occur in womens (Skinner, 2005; Hall, 2007; Roudebush et al., 2008). In old cows fewer follicles are recruited into the follicular wave, which results reduced oocyte ovulation and fecundity (Adams et al., 2008). Inadequate regulation or coordination of recruitment and development of primordial follicles can induce pathological states. For example, premature depletion of ovarian pool of primordial follicles induces premature ovarian failure (POF) and infertility (Skinner, 2005; Broekmans et al., 2006), which affects approximately 15%-20% of reproductive aged couples (Rougebush et al., 2008). On the contrary, intensive formation of small pre-antral follicles and early growing follicles, not reaching later stages of their development and ovulation are characteristics of polycystic ovarian syndrome (PCOS) (Franks et al., 2008).

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1.1.2. Pre-Ovulatory Changes and Ovulation Ovulation is the process of tissue remodeling by which the cumulusoocyte complex and follicular fluid escape the confines of the ovary and become available for fertilization (see reviews of Gougeon, 2004; Aerts and Bols, 2008a,b). Some hours before ovulation, ovarian cells undergo dramatic morphological and functional changes, including the resumption of meiosis by the oocyte. The oocyte nucleus, or germinal vesicle, undergoes a series of events that involve the destruction of its membrane (called germinal vesicle breakdown, GVBD), and meiosis continues from diplotene-dictyotene to the second metaphase (first polar body) stage. Meiosis is then again arrested and will proceed no further unless the ovulated egg is fertilized. Meiosis is described below. During these changes in the oocyte, the surrounding cumulus oophorus cells undergo mucification followed by expansion. The onset of mucification is marked by a dramatic increase in the secretion of the glycosaminoglycan hyaluronic acid into the extracellular spaces. Hyaluronic acid absorbs a large quantity of water and forms a bulky gel, causing the egg-cumulus complex to expand tremendously and leading to the dispersal of the cumulus cells. Cumulus expansion and the accumulation of hyaluronic acid are physiologically important as preparations for ovulation and subsequent

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fertilization: they allow the attachment and penetration of sperm, and the glycosaminoglycan induces the acrosome reaction in the sperm head prior to fertilization itself. Immediately before ovulation, proteolytic and collagenolytic enzymes degrade the basement membrane between the theca and granulosa layers of the follicle wall. This allows capillaries to penetrate the antrum for the first time and the granulosa and thecal cells begin to mix. There is also a complex series of tissue events within the follicle wall and adjacent parts of the ovarian stroma which strongly resemble those of the inflammatory reaction. Enzymes in the wall of the ovary above the protruding follicle are activated in response to granulosa-derived hormones (including prostaglandin F and progesterone) and products from the invading blood cells; this causes a hole to form in the ovarian surface, called the stigma or macula pellucida. (Irving-Rodgers and Rodgers, 2006). The follicular fluid is extruded through the stigma, under residual pressure from the collapsing follicle, taking with it the mature oocytecumulus complex which is then gathered by the fimbriae of the oviduct (Fallopian tube).

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1.1.3. Luteogenesis and Luteolysis After ovulation, the follicle wall in the majority of mammalian species develops into a new tissue called the corpus luteum. Its structure, life span and regulators are described in several reviews (Niswender et al., 2000, 2002; Stouffer, 2004; Meidan et al., 2005, Gadsby et al., 2006; Skarzynski et al., 2008). Corpus luteum is a large, rapidly growing but transient endocrine gland that secretes progesterone, estradiol and several protein hormones during the first part of the luteal phase of the cycle. These hormones prepare the uterine lining for implantation, and if the oocyte is fertilized and pregnancy ensues, the corpus luteum will continue to produce large amounts of progesterone, to maintain the condition of the uterus and support pregnancy. At the start of the luteinization of the ruptured follicle, a fibrin clot forms in the collapsed antrum (where the follicular fluid was previously located). This becomes a focus for the invasion of blood cells and the formation of a loose connective tissue in a process resembling that of post-inflammatory wound repair. Subsequently, a more solid tissue is established in which the mixing granulosa, theca (transforming into steroidogenic large and small luteal cells respectively), and non-endocrine stromal, vascular endothelial cells, fibroblasts, pericytes and intruding immune cells (lymphocytes, leucocytes and macrophages) are

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reorganized around an expanding network of capillaries. This is now the active corpus luteum. During luteinization, the granulosa cells undergo cytoplasmic expansion and increase in size, now being referred to as large luteal or granulosa-lutein cells. They have a high capacity for progesterone synthesis. The theca (or theca-interstitial) cells are also incorporated into the corpus luteum but are smaller and described as small luteal or theca-lutein cells. They secrete lower but still significant amounts of progesterone and may also produce androgens. The extent to which the large and small luteal cells intermingle and the microanatomy of the luteal tissue varies between species. As well as conditioning the uterus to support implantation and pregnancy, progestagens and other hormones from the corpus luteum limit the development of other follicles, thereby preventing maturation and ovulation until the corpus luteum regresses (luteolysis) (Meidan et al., 2005; Skarzynski et al., 2008). In the event of pregnancy, the corpus luteum survives for the whole of gestation or until the placenta takes over the bulk of hormone secretion, depending on the species. Luteolysis is prevented by signalling substances generated by implanted embryo. If the oocyte is not fertilized and implantation does not occur, the corpus luteum degenerates within a fixed interval of time characteristic of the species. Luteolysis consists of two phases, functional luteolysis and structural luteolysis. A rapid functional regression of corpus luteum is characterized by a decrease of progesterone production, whish induce structural regression (Rueda et al. 2000). During structural luteolysis, luteal cells undergo apoptosis Histologically, the first indication of this is the apoptotic shrinkage of the large luteal cells. By contrast the small cells appear selectively hyperstimulated during early luteolysis. At the later stages of luteolysis both cell types become apoptotic and are eventually destroyed, leading to the morphological regression of the corpus luteum (Niswender et al., 2000). All that remains is a nodule of dense, functionless connective tissue called the corpus albicans For primates, ruminants, rodents and the majority of other mammals, the ovarian cycle may therefore be described as having two basic phases: the follicular and luteal phases. The phases may be temporally distinct (for example, in humans), or there may be limited follicular development throughout the cycle with only the later stages of maturation being inhibited by the corpus luteum (for example, ruminants). An alternative description of the cycle, based on the behavior of the female and the cytological condition of the reproductive tract, but reflecting events in the ovary, includes the following phases: proestrus (start of follicular

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phase, luteolysis, ovaries secrete estrogen and small amounts of progesterone), estrus (completion follicular maturation, major secretion of estrogen, ovulation, mating, egg fertilization), metestrus (early luteal phase, time between ovulation and formation of corpus luteum, switch from estrogen to progesterone secretion) and diestrus (active corpus luteum, highest rate of progesterone secretion) (Fig.4). Anoestrus refers to times in an animal‟s or human‟s life when estrous cycles are absent due to lack of follicle development, follicles atresia, existence of persistent pre-ovulatory follicle or post-ovulatory persistent corpus luteum. Such state occurs before puberty, during pregnancy, at non-breeding times of year, or as a result of age, disease or inadequate stimulation by hormones (Peter et al., 2009).

Figure 4. Terms and concepts related to stages within the follicular and luteal phases in association with respective changes in circulating concentrations of estradiol (E2), progesterone (P4) and preovulatory (OV) gonadotropin surge during the bovine estrous cycle (from Peter et al., 2009).

In humans, there is no estrous cycle as such because changes in sexual receptivity and genital appearance are absent or less evident than they are in most other species. There is a continuous sequence of alternating luteal and follicular phases of roughly equal length, separated by menstruation (designated as starting on Day 1 of the cycle) and ovulation (at “mid-cycle”). In other mammals, the start of the follicular phase (the start of proestrus) is designated by convention as Day 1 of the cycle. Some mammals (for example, rabbits) ovulate only in response to mating. Others (rodents) form a true corpus luteum only if the embryo implants and pregnancy takes place: no true

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corpus luteum appears after ovulation during an infertile ovarian cycle. Yet others (cats) may have an extended luteal phase (“pseudopregnancy”) following an infertile mating. Many animals, including birds and lower vertebrates, do not form a corpus luteum at all.

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References Adams GP, Jaiswal R, Singh J, Malhi P. Progress in understanding ovarian follicular dynamics in cattle. Theriogenology. 2008 69:72-80. Aerts JM, Bols PE. Ovarian follicular dynamics. A review with emphasis on the bovine species. Part II: Antral development, exogenous influence and future prospects. Reprod Domest Anim. 2008b 45:180-187. Aerts JM, Bols PE. Ovarian follicular dynamics: A review with emphasis on the bovine species. Part I: Folliculogenesis and pre-antral follicle development. Reprod Domest Anim. 2008a 45:171-179. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update. 2006 12:685-718. Craig J, Resaca M, Wang H, Resaca S, Thompson W, Zhu C, Kostunica F, Tsang BK. Gonadotropin and intra-ovarian signals regulating follicle development and atresia: the delicate balance between life and death. Front Biosci. 2007 12:3628-3639. Feng WG, Sui HS, Han ZB, Chang ZL, Zhou P, Liu DJ, Bao S, Tan JH. Effects of follicular atresia and size on the developmental competence of bovine oocytes: a study using the well-in-drop culture system. Theriogenology. 2007 67:1339-1350. Fortune JE. The early stages of follicular development: activation of primordial follicles and growth of preantral follicles. Anim Reprod Sci. 2003 78:135-163. Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update. 2008 14:367-378. Gadsby J, Rose L, Sriperumbudur R, Ge Z. The role of intra-luteal factors in the control of the porcine corpus luteum. Soc Reprod Fertil 2006 Suppl. 62:69-83.

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Gougeon A. Dynamics of human follicular growth: morphologic, dynamic, and functional aspects. In: The Ovary. Second Edition. (Leung PCK and Adash EY eds.) Elsevier-Academic Press, Amsterdam et al. 2004, pp. 2543. Hall JE. Neuroendocrine changes with reproductive aging in women. Semin Reprod Med. 2007 25:344-351. Hrometz SL, Gates VA. Review of available infertility treatments. Drugs Today (Barc) 2009 45:275-291. Hunter, Robinson RS, Mann GE, Webb R. Endocrine and paracrine control of follicular development and ovulation rate in farm species. Anim Reprod Sci. 2004 82-83:461-477. Hutt KJ, Albertini DF An oocentric view of folliculogenesis and embryogenesis. Reprod Biomed Online. 2007 14:758-764. Irving-Rodgers HF, Rodgers RJ. Extracellular matrix of the developing ovarian follicle. Semin Reprod Med. 2006 24:195-203. Lonergan P. State-of-the-art embryo technologies in cattle. Soc Reprod Fertil 2007 Suppl.64:315-325. McLaughlin EA, McIver SC. Awakening the oocyte: controlling primordial follicle development. Reproduction. 2009 137:1-11. Meidan R, Levy N, Kisliouk T, Podlovny L, Rusiansky M, Klipper E. The yin and yang of corpus luteum-derived endothelial cells: balancing life and death. Domest Anim Endocrinol. 2005 29:318-328. Mermillod P, Dalbiès-Tran R, Uzbekova S, Thélie A, Traverso JM, Perreau C, Papillier P, Monget P. Factors affecting oocyte quality: who is driving the follicle? Reprod Domest Anim. 2008 43 Suppl 2:393-400. Mihm M, Evans AC. Mechanisms for dominant follicle selection in monovulatory species: a comparison of morphological, endocrine and intraovarian events in cows, mares and women. Reprod Domest Anim. 2008 43 Suppl 2:48-56. Miyano T, Manabe N. Oocyte growth and acquisition of meiotic competence. Soc Reprod Fertil Suppl. 2007 63:531-538. Niswender GD, Juengel JL, Silva PJ, Rollyson MK, McIntush EW. Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev 2000 80: 1–29. Niswender GD. Molecular control of luteal secretion of progesterone. Reproduction. 2002 123:333-339. Oktem O, Oktay K. The ovary: anatomy and function throughout human life. Ann N Y Acad Sci. 2008 1127:1-9.

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Peter AT, Levine H, Drost M, Bergfelt DR. Compilation of classical and contemporary terminology used to describe morphological aspects of ovarian dynamics in cattle. Theriogenology. 2009 71:1343-1357. Roudebush WE, Kivens WJ, Mattke JM. Biomarkers of ovarian reserve. Biomark Insights. 2008 3:259-268. Rueda BR, Hendry IR, Hendry WJ III, Fong HW, Stormashak F, Slaydenlayden OD, Davis JS. Decreased progesterone level and progesterone receptors antagonists promote apoptotic cell death in bovine luteal cells. Biol Reprod 2000 62:269–276. Skarzynski DJ, Ferreira-Dias G, Okuda K. Regulation of luteal function and corpus luteum regression in cows: hormonal control, immune mechanisms and intercellular communication. Reprod Domest Anim. 2008 43 Suppl 2:57-65. Skinner MK. Regulation of primordial follicle assembly and development. Hum Reprod Update. 2005 11:461-471. Stouffer RL. The function and regulation of cell populations comprising the corpus luteum during the ovarian cycle. In: The Ovary. Second Edition. (Leung PCK and Adash EY eds.) Elsevier-Academic Press, Amsterdam et al. 2004, pp. 169-184. Tingen C, Kim A, Woodruff TK . The primordial pool of follicles and nest breakdown in mammalian ovaries. Mol Hum Reprod. 2009 15:795-803. Webb R, Campbell BK. Development of the dominant follicle: mechanisms of selection and maintenance of oocyte quality. Soc Reprod Fertil. Suppl. 2007 64:141-163.

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Chapter 2

Oocytes and their Maturation Abstract This chapter reviews the basic processes related to nuclear maturation (meiosis) and cytoplasmic maturation of oocytes.

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2.1. Oocyte Oocytes (eggs) are cells specialized for sexual reproduction, the main result of which is the pooling of genetic information from two organisms. As mentioned above, oocytes arise by mitosis from embryonic germ cells located in the embryonic ovarian cortex. Shortly before or after birth, mitotic activity ceases. The germ cells enter the prophase of meiosis and become oogonia, the precursors of oocytes. During subsequent growth and maturation, oogonia develop into mature oocytes. As with sperm, the maturation of oocytes includes both nuclear and cytoplasmic maturation. To achieve the status of germ cell, a diploid somatic cell is transformed into a haploid cell. Fusion with another germinal haploid cell (that is, fertilization of oocyte by sperm), results in the formation a diploid cell (zygote) containing a mixed genome derived from both parent cells. The transformation of somatic cells into germinal cells includes a reduction in the number of chromosomes during the course of meiotic division (nuclear maturation; Fig. 1). There are also changes in cytoplasm which result in the accumulation of substances necessary for fertilization and for the formation of the zygote and first daughter somatic cells (cytoplasmic maturation). In

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contrast to male gametes (sperm), female gametes (oocytes) contain much more cytoplasm, organelles and stored material; this is due to unequal division (see below) and intensive protein synthesis at particular stages of the meiotic cycle.

Figure 1. Transformation of diploid somatic cells to haploid gametes (eggs and sperm) during meiosis and return to diploid state after fertilization and zygote formation (http://faculty.clintoncc.suny.edu/faculty/Michael.Gregory/files/Bio%20101/Bio%201 01%20Lectures/Meiosis/meiosis.htm).

2.2. Oocyte Nuclear Maturation Nuclear maturation of oocytes and its regulation is described in some comprehensive reviews (Eppig et al., 2004; Deckel, 2005; van den Hurk and Zhao, 2005; Grøndahl, 2008; Kimura et al., 2008; http://www.vetscite.org/ publish/items/000552/index.html). The nuclear maturation of an oocyte occurs during meiosis. The phases of the cell cycle in meiosis are similar to those of mitosis (the division of somatic cells; Fig. 2):  synthetic (S) phase: the phase of duplication of DNA, synthesis of molecules required for division of mother cells, and distribution of genetic material between two daughter cells,  mitotic or meiotic (M) phase: the phase of division of chromosome and cytoplasm, and their distribution between daughter cells, and

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 growth or gap (G) phases between these processes (G1 phase before, and G2 phase after, the S phase).

Figure 2. Phases of the mitotic cell cycle (http://ghs.gresham.k12.or.us/science/ ps/sci/soph/cells/cycle/cyclerev.htm)

In contrast to mitosis, the S phase of meiosis is followed not by one, but by two subsequent divisions without an intermediary S phase, resulting in the formation of haploid rather than diploid cells. The meiotic cell cycle is preceded by a premeiotic interphase in which the nuclear material is duplicated so that the cell, like all somatic cells, is diploid. There are then two cycles of meiotic division, meiosis I and meiosis II, separated by an interval called interkinesis. The meiotic phases have the same names as those of mitosis, plus an indicator of the division number: meiosis I: prophase I, metaphase I, anaphase I, and telophase I meiosis II: prophase II, metaphase II, anaphase II, and telophase II The main stages of meiosis are characterized by the following morphological features:

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Alexander V. Sirotkin  Diplotene – prophase of the first meiotic division; chromatin is diffuse, chromosomes are despiralised and the nuclear membrane (germinal vesicle, GV) is present.  Diakinesis – the end stage of prophase of the first meiotic division; chromosomes (four copies of each - tetrads) are condensed and germinal vesicle breakdown (GVBD) occurs.  Metaphase I – maximal condensation of chromosomes and their localization to the equatorial area of oocyte; the end of GVBD; gap junctions between the oocyte and its cumulus oophorus cells break down.  Anaphase I – the formation of a meiotic spindle and the separation of condensed chromosomes towards the poles of the oocyte.  Telophase I – chromosomes are localized at the poles of the oocyte; one of group of chromosomes starts to degenerate and form polar body I which is expelled to the perivitelline area between oocyte and zona pellucida.  Metaphase II – start of the second meiotic division of the surviving chromosome group. Chromosomes (two copies of each – diads) are localized in the equatorial area of the oocyte and a meiotic spindle is present.  Anaphase II – telophase II ; this is initiated by spermatozoa entering the cytoplasm of oocyte; it resembles anaphase I-telophase I.

In the first meiotic division, homologous chromosomes pair up and exchange segments, a process called recombination. The number of cells is then doubled but the number of chromosomes is not, resulting in half the number of chromosomes per cell. The second meiotic division is like mitosis in that the number of chromosomes does not get reduced. The meiotic production of male germ cells (spermatozoa) results in the formation of four haploid cells for each initial diploid cell. In contrast, the production of female germ cells results in just one oocyte from each diploid cell. At each meiotic division, one of the pair of daughter cells develops whist the other, the “polar body”, degenerates (Fig. 3). The meiotic distribution of cytoplasm between the daughter cells is unequal: the maturing cell receives the majority with a small amount going to form the polar body. The polar body with its degenerating chromosomes is expelled to the surface where it remains functionless and eventually disappears. During and after these events, chromosomes (each is present in one copy – monad) are despiralised within the haploid pronucleus. At fertilization, this fuses with a male haploid

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pronucleus to form the diploid nucleus of a zygote and a new diploid organism.

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Figure 3. Division of cytoplasm during oocyte maturation: first and second meiotic divisions http://faculty.clintoncc.suny.edu/faculty/Michael.Gregory/files/Bio%20101/ Bio%20101%20Lectures/Meiosis/meiosis.htm)

In contrast to sperm, meiosis in oocytes is a prolonged process: after their formation within the embryo, oocytes remain at the G2 (diplotene-dictyotene) stage of meiosis I (with despiralised chromosomes surrounded by a germinal vesicle) until the animal reaches reproductive age. As the ovaries become active, oocytes leave this prolonged resting state and resume their growth and cytoplasmic maturation. Oocytes resume meiosis sequentially, in association with cycles of follicular development. Up to preovulatory period, oocytes remain at diplotene-dictyotene stage of meiosis. Before ovulation, the oocyte nucleus, or germinal vesicle, undergoes a series of events that involve the destruction of its membrane (called germinal vesicle breakdown, GVBD), and meiosis continues from diplotene-dictyotene to the second metaphase (first polar body) stage. Meiosis is then again arrested and will proceed no further unless the ovulated egg is fertilized. Thus, between the onset of puberty and completion of folliculogenesis, each maturing oocyte undergoes GVBD, chromatin condensation (formation chromosomes) and two chromosome divisions; in other words, it progresses from diplotene-dictyotene through diakinesis, metaphase I, telophase I, metaphase II, anaphase II and telophase II if the ovulated egg is fertilized.

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2.3. Oocyte Cytoplasmic Maturation Cytoplasmic maturation refers to oocyte growth, changes in structure and distribution of oocyte organelles and the accumulation of biologically active substances necessary for further development. Among the organelles the changes in position and structure of mitochondria, ribosomes, endoplasmic reticulum, cortical granules, Golgi complex assume different positions during the transition from the germinal vesicle stage to metaphase II are described. The cytoskeletal microfilaments and microtubules present in the cytoplasm promote these movements and act on chromosome segregation, the most important part of nuclear maturation. Ribosomes produced peptides necessary for oocyte maturation and further developoment. Furthermore, cytoplasmic maturation includes storage of ATP, mRNAs, proteins and transcription factors (Brevini et al., 2007; Miyano and Manabe, 2007; Ferreira et al., 2009). One of such proteins could be transport/motor protreins kinesins, whose amount and localisation changes during oocyte nuclear maturation. An other groups could be RNA binding proteins Staufen, which recognise and binds RNAs for their transport (Brevini et al., 2007). After reinitiation of nuclear maturation, protein synthesis is rapidly activated and substantial part of the mRNA is either deadenylated or degraded. The accumulated material enables successful maturation and fertilization, and initial cell division in zygotes up to the 8- to 16-cell stage (Aerts and Bols, 2008). Synchronisation of cytoplasmic and nuclear maturation is a prerequisite of oocyte competent to further development, which should be taken into account by oocyte in-vitro maturation and embryo production (Eppig et al., 2004; Mermillod et al., 2008). Storage of substances in cytopolasm induces oocyte growth. The growth of mammalian oocytes occurs in two distinct and characteristic stages. In the first, the growth is temporally correlated with that of the follicle in which it develops. In the second phase, the size of the oocyte remains constant, despite the continuing growth of follicle up to its pre-ovulatory condition. Macromolecules and organelles stored in oocytes during the first growth phase are responsible for progression through meiosis and will be required subsequently for the decondensation of penetrating spermatozoa, the formation of a male pronucleus, fertilization, the formation of the zygote and embryo up to the 6-8 blastomere stage ( van den Hurk and Zhao,2005). The successful growth and maturation of the oocyte within the follicle depend on the surrounding follicular somatic cells of the cumulus and

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granulosa layers. Somatic cell-oocyte interactions via gap junctions provide oocytes with energy and substrates for metabolism and for future divisions, fertilization and the early stages of embryogenesis (Feng et al., 2007; Mermillod et al., 2008). The materials supplied include nucleosides, amino acids, phospholipids and ions, along with paracrine/endocrine signaling substances which control oocyte maturation (meiosis regulating factors including cAMP, MPF etc: see below). Any deficiency in the somatic cells or defects in the gap junctions between these cells and the oocyte will prevent optimal oocyte growth and maturation; this may result in an inability of the oocyte to undergo fertilization or may reduce the competence of the zygote and early embryo to embark successfully on further development. Thus the health of the follicle has a significant influence on the oocyte‟s potential to give rise to an offspring. The direct involvement of the follicle in oocyte development represents a route by which the health and physiological status of the female animal may determine the eventual quality of her offspring and the overall efficiency of reproduction (Feng et al., 2007; Webb and Campbell, 2007; Mermillod et al., 2008). For scientists studying reproduction in the laboratory and embryologists carrying out assisted reproduction procedures, it is essential to obtain the best quality oocytes and to optimize the conditions under which they are handled and manipulated. It should also be noted that the interrelationships between oocyte and follicular cells are bi-directional. The oocyte secretes specific signaling molecules (mainly growth factors and hormones) which can influence a range of ovarian processes including folliculogenesis and expansion, the secretion of steroid hormones by the cumulus oophorus, and the proliferation, differentiation, secretory activity and luteinization of granulosa cells (Hutt and Albertini, 2007, Webb and Campbell, 2007; Aerts and Bols, 2008; McLaughlin and McIver, 2009). Maturation and fertilisation of oocytes is a key process in reproduction. Understanding and regulation of this process is necessary for induction of oocyte maturation in vivo and in vitro in induction of ovarian cycle and superovulation, in vitro oocyte maturation, fertilisation and embryo production and transfer (Lonergan et al., 2007; Grøndahl, 2008; Hashimoto, 2009), as well as in treatment of infertility and other reproductive disorders including PCOS, consequence of cancer therapy etc. (Grøndahl, 2008; Hrometz and Gates, 2009) in assisted reproduction, biotechnology, human and veterinary medicine.

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References Aerts JM, Bols PE. Ovarian follicular dynamics: a review with emphasis on the bovine species. Part I: Folliculogenesis and pre-antral follicle development. Reprod Domest Anim. 2008 45:171-179. Brevini TA, Cillo F, Antonini S, Gandolfi F. Cytoplasmic remodelling and the acquisition of developmental competence in pig oocytes. Anim Reprod Sci. 2007 98:23-38. Dekel N. Cellular, biochemical and molecular mechanisms regulating oocyte maturation. Mol Cell Endocrinol. 2005 234:19-25. Eppig JI, Vivelros MM, Martin-Bivens C, De La Fuente R. Oocyte maturation and ovulation. In: The Ovary. Second Edition. (Leung PCK and Adash EY eds.) Elsevier-Academic Press, Amsterdam et al. 2004, pp. 113-129. Feng WG, Sui HS, Han ZB, Chang ZL, Zhou P, Liu DJ, Bao S, Tan JH. Effects of follicular atresia and size on the developmental competence of bovine oocytes: a study using the well-in-drop culture system. Theriogenology. 2007 67:1339-1350. Ferreira EM, Vireque AA, Adona PR, Meirelles FV, Ferriani RA, Navarro PA Cytoplasmic maturation of bovine oocytes: structural and biochemical modifications and acquisition of developmental competence. Theriogenology. 2009 71:836-848. Grøndahl C.Oocyte maturation. Basic and clinical aspects of in vitro maturation (IVM) with special emphasis of the role of FF-MAS. Dan Med Bull. 2008 55:1-16. Hashimoto S.Application of in vitro maturation to assisted reproductive technology. J Reprod Dev. 2009 55:1-10. Hrometz SL, Gates VA. Review of available infertility treatments. Drugs Today (Barc). 2009 45:275-291. Hutt KJ, Albertini DF. An oocentric view of folliculogenesis and embryogenesis. Reprod Biomed Online. 2007 14:758-764. Kimura N, Hoshino Y, Totsukawa K, Sato E. Cellular and molecular events during oocyte maturation in mammals: molecules of cumulus-oocyte complex matrix and signalling pathways regulating meiotic progression. Soc Reprod Fertil Suppl. 2007 63:327-342. Lonergan P. State-of-the-art embryo technologies in cattle. Soc Reprod Fertil 2007 Suppl.64:315-325 McLaughlin EA, McIver SC. Awakening the oocyte: controlling primordial follicle development. Reproduction. 2009 137:1-11.

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Mermillod P, Dalbiès-Tran R, Uzbekova S, Thélie A, Traverso JM, Perreau C, Papillier P, Monget P. Factors affecting oocyte quality: who is driving the follicle? Reprod Domest Anim. 2008 43 Suppl 2:393-400. Miyano T, Manabe N. Oocyte growth and acquisition of meiotic competence. Soc Reprod Fertil Suppl. 2007 63:531-538. van den Hurk R, Zhao J. Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. Theriogenology. 2005 63:1717-1751. Webb R, Campbell BK. Development of the dominant follicle: mechanisms of selection and maintenance of oocyte quality. Soc Reprod Fertil Suppl. 2007 64:141-163.

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Chapter 3

Extracellular Regulators of Ovarian Functions

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Abstract This chapter reviews the most known extracellular regulators of ovarian functions. First sub-chapters shortly outline classification, nomenclature and interrelationships between of biological signaling substances including hormones and hormone-like substances. Next sub-chapters represent short description of the following extracellular regulators of ovarian functions: gonadotropin-releasing hormone (GnRH), gonadotropins FSH and LH, steroid hormones progestins, androgens and estrogens, growth hormone (GH), prolactin, oxytocin and its analogues, leptin, ghrelin, obestatin, prostaglandins, indoleamines serotonin and melatonin, insulin-like growth factors (IGFs), epidermal growth factors (EGFs), vascular endothelial growth factor (VEGF), thrombopoietin (TPO), erytropoietin (EPO), hepatocyte growth factor (HGF), growth factors of Hedgehog, Wnt, and Notch families, cytokines colony stimulating factors (CSFs), tumor necrosis factors (TNFs), interleukines (ILs), inhibin, activin, follistatin, antiMullerian hormone (AMH), bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). Basic information concerning expression of these molecules and their receptors in the ovary, their action on ovarian cell proliferation, apoptosis, ovarian follicle growth and development, secretory activity, possible practical application of these substances and references to key related publications are provided.

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3.1. Function and Classification of Biological Signaling Substances Regulation to adapt to changed internal and external conditions is the basic feature of living systems. Regulatory chemicals produced by cells are intended for coordination of internal events and for cell-to-cell interactions. Bioregulation probably has its origin in local secretions that affects nearby cells or internal cellular processes. The evolution of multicellular organisms was associated with evolution of intra- and inter-cellular communication, which included appearance of cells specialized for production of signaling substances and their transport to other, target cells. Contemporary classifycation of regulatory/signaling substances is based on their chemical structure or precursor (peptides and nonpeptides, monoamines, gases, acids, aminoacids and their derivates a.o.), function (for example, hypothalamic releasing and inhibiting hormones, gonadotropins etc.), solubility in lipids and water (lipophylic or lipid-soluble like, which can cross the cell membrane or bind to membrane receptors, and hydrophilic, water-soluble molecules that bind to receptors on the cell surface because they cannot diffuse across cell membrane) and target of secretion (intracellular fluid, synaptic space, blood and other transport fluids, environment etc.). According to this classification, there are the following types of signaling substances (Norris, 2006): 1. Neurotransmitters (substances secreted by neurons into synaptic space), 2. Neuromodulators (neurotransmitters modulating sensitivity of postsynaptic cell to other neurotransmitters), 3. Neurohormones (secreted by neurons into blood, lymph or cerebrospinal fluid), 4. Hormones (secreted by nonneuronal cells into blood), 5. Cytocrine regulators (local regulators secreted into the surrounding extracellular fluid), 6. Paracrine regulators (secreted by cells that affect other cell types), 7. Autocrine regulators (secreted by cells that affect emitting cells), 8. Intracrine regulators (intracellular messengers) and 9. Semiochemical regulators (secreted into environment). It is accepted, that multicellular organism has three basic regulatory systems (endocrine, nervous and immune), but close functional interr

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elationships, overlapping the functions and use of sometimes similar signaling substances makes such classification of regulatory systems rather conventional than functional.

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3.2. Hormones and Hormone-Like Substances Hormones (from the Greek, hormao - “to spur on”) are chemical messengers secreted by cells (single cells, tissues and organs specializing to production of hormones, so called endocrine glands) in one part of a multicellular organism that travel to and coordinate the activities of different cells, providing a value to the whole organism. In animals, an hormone is usually carried from its site of release to the target cell by the blood and other fluids (lymph, cerebrospinal fluid, interstitial fluid etc.), sometimes over large distances through the body. In in-vitro systems, hormone-producing cells release their products into the culture medium, which is widely used for their characterisation and studies of control mechanisms. The time-dependent accumulation of some hormones and their binding protein by whole cultured ovarian follicles is shown in Fig.1. The hormone-producing endocrine system includes peripheral hormoneproducing cells (located in practically all tissues) and a number of integrated organ and tissue systems including the hypothalamo-hypophysial axis. The latter includes the pituitary gland (hypophysis) and the hypothalamus (a basal part of the brain) and provides one of the main links between the endocrine system and the central nervous system. Hypothalamic endocrine cells produce “releasing” and “inhibiting” hormones (sometimes also called factors) into a local region of the circulation which takes them directly to the cells of the anterior pituitary gland. Here they stimulate or inhibit the secretion of “tropic” hormones into the general circulation. The products of the anterior pituitary gland regulate a range of peripheral organs and are often described in the context of homeostasis, or the maintenance of the stability of the internal environment. The posterior part of the pituitary is actually a down growth of the hypothalamus itself. It stores and releases small peptide hormones of hypothalamic origin (oxytocin, vasopressin and their analogues).

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Alexander V. Sirotkin Hormone level (pg or ng /ml medium)

28

30

25

OT

20

15

P 10

5

IGFBP-3 0

0

1

2 3 4 Days of culture

6

8

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Figure 1. Time-dependent accumulation of progesterone (P), oxytocin (OT) and insulin-like growth factor binding protein 3 (IGFBP-3) in incubation medium conditioned by porcine ovarian follicles. Values are mean  SEM. (from Sirotkin et al., 2003).

The efficiency of hormone delivery from the site of its production to the target cells depends on hormone metabolism, rates of clearance of hormone from the circulation, and whether hormone is free in the circulation or bound to transport/binding proteins. Some peptide hormones (growth hormone, GH, insulin-like growth factors, IGF-I and IGF-II, vasopressin and oxytocin) and the major steroid and thyroid hormones are transported bound to plasma binding proteins. Binding proteins in circulation can inactivate, but prevent hormone from degradation. Free hormone, which is not bound to binding protein, is available for receptor binding and exertion its biological function. Therefore, hormone effect can be regulated not only by hormone production and reception, but also by its interrelationship with binding protein, metabolism and degradation. According to solubility and chemical structure, there are three categories of vertebrate hormones: 1. Small lipophilic (lipid-soluble) molecules that are able to diffuse across the plasma membrane of the target cell and interact with intracellular receptors of the cytoplasm or nucleus. The resulting complexes bind to transcription-control regions in DNA, affecting

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expression of specific genes. The steroid hormones and thyroxine are two examples of this type. 2. Lipophilic molecules that bind to cell-surface receptors, such as the eicosanoids. 3. Hydrophilic (water-soluble) molecules that bind to receptors on the cell surface because they cannot diffuse across cell membrane. There are two subgroups: (a) peptide hormones, such as growth hormone and gonadotropins, which range in size from a few amino acids to protein-size compounds; and (b) small charged molecules, such as epinephrine and histamine, derived from amino acids, which function as both hormones and neurotransmitters. Hormonal signaling typically involves the following six steps:

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1. 2. 3. 4.

Biosynthesis of the hormone in a specialized tissue. Storage and secretion of the hormone. Transport of the hormone to the target cell(s). Recognition of the hormone by an associated cell membrane or intracellular receptor protein. 5. Relay and amplification of the received hormonal signal via a signal transduction process. 6. Removal of the signal, which often involves degradation of the hormone, to terminate the cellular response. Some other signaling substances called growth factors, eicosanoids, cytokines and indoleamines can be considered as hormones because they have all characteristics of hormones listed above, although some these substances can also act as non-hormonal signaling substances (neurotransmitters, neuromodulators etc.). Growth factors is a large and heterogenous group of peptide hormones, whose first described effects were related to tissue growth, but whose act as both hormones and local paracrine/autocrine factors. Eikosanoids are signaling lipid molecules, whose act as paracrine, autorcrine and endocrine signaling substances. Cytokines are proteins, peptides, or glycoproteins, whose first identified production and action was related to immune system, but whose can act as hormones in control of wide array of cells and processes. Indoleamines, product of aminoacid tryptophan (for example, serotonin and is derivates) can act as neurotransmitter, hormone and growth factor. In addition, some molecules, previously thought to act only as substrates of by-products of metabolic processes (fatty acids, amino acids, bile acids, nitric oxide), are now

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known as cell-to-cell signaling molecule, i.e. substance with hormone-like action (Dhillo et al., 2006). Hormones, hormone-like substances mentioned above and mediators of their action are an important part of signalling mechanism, by which organism adapt to external or internal factors by changing activity of corresponding genes. Such signalling system includes 1. Action of external or internal factor to its receptor (which usually belongs to nervous system). 2. Transfer of signal (usually by neurones) to hormone-producing cells. 3. Changes in release of hormone and/or its binding protein 4. Binding of hormone to specific receptor on the surface (peptide hormones) or in nucleus (non-peptide hormones) of target cells 5. Peptide hormone-receptor complex affects intracellular protein kinases – enzymes catalysing protein phosphorylation and, therefore, their biological activity. In addition to protein kinases, they could affect protein phosphatases (dephosphorylating enzymes) and proteases. 6. Peptide hormones-related protein kinases phosphorylate/affect activity of transcription factors, whose control activity of specific genes and production of genes-encoding proteins. 7. Non-peptide hormone-receptor complex acts as transcription factor binds to hormone response element of DNA or affects other growth factors to activate specific genes and to increase production of their proteins. 8. The influence of hormone-receptor complex on RNA interference is not to be excluded. Therefore, hormones, growth factors, cytokines, indoleamines, eikosanoids are extracellular regulators of ovarian cell functions mediating effect of external factors on the cells. Protein kinases are intracellular regulators of ovarian functions mediating transfer of signal from extracellular factors to the nucleus, the main site of genes. Activity of specific genes is controlled immediately by large family of regulators including coactivators, chromatin remodelers, histones and their acetylases, deacetylases, methylases, transcription factors, RNA interference and others. The most known direct regulators of genes involved in control of ovarian functions are transcription factors and RNA interference.

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The proteins, whose production or activity is altered by these signaling systems, could be other hormones, local growth factors, cytokines and eicosanoids (who‟s in turn act as hormones) or proteins controlling cell proliferation, apoptosis, differentiation and other functions. Downstream molecules can both up- and down-regulate the upstream structures by either positive or negative feedback mechanisms. The following is a short summary of the major roles of extracellular signalling molecules (hormones, growth factors, cytokines, indoleamines eikosanoids) within the ovary.

3.3. Extracellular Regulators of Ovarian Functions

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3.3.1. Gonadotropin-Releasing Hormone (GnRH) Gonadotropin releasing hormone (GnRH) is a secretory decapeptide which production and release in a pulsatile manner was first detected in hypothalamus. Subsequently its production in other tissues including the ovary has been demonstrate. Fourteen structural variants and three different forms of GnRH, named as hypothalamic GnRH or GnRH-I, mid brain GnRH or GnRHII and GnRH-III across various species of protochordates and vertebrates have been recognised (Leung and Cheng, 2004). Known is the role of GnRH in control of production and release of pituitary gonadotropins. Both FSH and LH are stimulated by this peptide. Very important is not only amount of released GnRH, but also the frequency of pulses of GnRH release. Different pattern of release of these two gonadotropins (see below) is due to additional control mechanisms – different response to feedback action of steroid hormones, as well as inhibin and activin/follistatin system, whose controls predominantly FSH, but not LH release (see below). In addition, extra-hypothalamic GnRH, GnRH receptors and action in various reproductive tissues including ovaries have been demonstrated (Leung and Cheng, 2004; Ramakrishnappa et al., 2005). Its presence and action is associated with ovarian state. For example, GnRH is more abundantly present in ovarian carcinomas, than in normal ovaries. GnRH-II and its receptors appears to be predominantly expressed in extra pituitary reproductive tissues. Production of ovarian GnRHs and their receptors are controlled by ovarian steroids, gonadotropins and melatonin

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(Leung and Cheng, 2004) suggesting direct and feedback control of intraovarian GnRH system. In the ovary, GnRH-I and Gn-RH-II are considered to act by autocrine or paracrine manner and regulate ovarian steroidogenesis by having stimulatory as well as inhibitory effect on the production of progesterone, testosteron, estradiol, oxytocin, vasopressin, cAMP, cGMP and apoptosis in ovarian follicle and corpus luteum. Furthermore, GnRH-I is able to decrease (Leung and Cheng, 2004) or increase (Sirotkin et al., 2003, Ramakrishnappa et al., 2005) the number of LH/hCG receptors and the response of granulosa cells and their response to gonadotropins. Furthermore, GnRH-I can be either direct inhibitor (Leung and Cheng, 2004) or stimulator (Sirotkin et al., 2003) of release of progesterone, estradiol, oxytocin, vasopressin, cAMP, cGMP by ovarian cells and promoter of oocyte maturation (Motola et al., 2006). GnRH-I is potent promoter of ovarian cella apoptosis (Leung and Cheng, 2004). The existence of different GnRH forms and different effects of different GnRH analogues on pituitary and ovary indicates the presence of distinctive cognate receptors types may contribute to the development of new generation of GnRH analogues with highly selective and controlled action on different reproductive tissues. At present GnRH analogues are used mainly for control of ovarian cycle via changes in gonadotrpin surge (Hunter et al., 2004). Luteal phase supplementation with GnRH analogues alters hormonal profiles, significantly induces oocyte maturation, improves clinical outcomes in in-vitro fertilization cycles, especially in patients who are at increased risk for ovarian hyperstimulation syndrome (DiLuigi and Nulson, 2007). Due to ability to suppress proliferation of ovarian carcinima cells, and control other ovarian functions, treatment of malignant and other ovarian disorders by GnRH analogues is considered too (Leung and Cheng, 2004; Ramakrishnappa et al., 2005).

3.3.2. Gonadotropins The most known gonadotropins are pituitary gonadotropins FSH and LH and the placental homologue of LH, human chorionic gonadotropin (hCG). These glycoprotein hormones consisting of two peptide subunits (common alpha subunit and hormone-specific beta subunit) are produced by anterior pituitary, leucocytes, placenta and some other tissues. Their production can be regulated by hypothalamic gonadotropin-releasing hormone (GnRH, stimulation), gonadal steroid hormones (stimulatory or inhibitory feedback mechanisms), gonadal peptide hormones – inhibin (inhibits FSH), activin

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(activates FSH) a.o., as well as some non-gonadal hormones (for example, leptin, which stimulates gonadotropins release). 3.3.2.1. FSH FSH receptors are located in granulosa cells. Polymorphism in FSH receptor affects responsibility of the ovary to FSH. It should be taken into account by induction of ovulation in patients by FSH (Huhtaniemi, 2004; Wunsch et al., 2007). Reports concerning effect of inactivating FSH receptor mutations are contradictory, but arrest of pubertal maturation and follicular maturation at primary strage has been observed (Huhtaniemi, 2004). Further studies demonstrated important role of FSH in ovarian folliculogenesis. FSH stimulates growth of antral follicles and the formation of a large pre-ovulatory follicle, as well as the LH receptors in this follicle that, because of its FSHdependent maturation, is capable of ovulation and forming a corpus luteum in response to the mid-cycle surge of LH. The increase in plasma FSH during luteo-follicular transition is the basis for follicle selection. The rise of FSH to the threshold concentration represents stimulates growth of the most sensitive follicles (see below) (Palermo, 2007; Mihm and Evans, 2008). Recently a new, miRNA-dependent (see below) mechanism of FSH action on ovarian follicullogenesis has been detected: FSH inhibited the expression of some miRNAs (mir-143, let-7a, mir-125b, let-7b, let-7c, mir-21), whose could be involved in control of ovarian follicullogenesis (Yao et al., 2009). The ability of FSH to promote ovarian follicullogenesis can be due to its stimulatory action on ovarian cell proliferation (Sirotkin et al., 2008), probably due to increased production of IGF-I and/or cAMP (Sirotkin et al., 2003) or receptor to BMP, promoter of ovarian folliculogenesis (see below) (Wang and Roy, 2009). Furthermore, the inhibitory effect of FSH on ovarian cell apoptosis has been reported (Jiang et al., 2003). FSH is able to promote release of steroid hormones, IGF-I, oxytocin, TNF alpha, cGMP and oocyte manuration (Jiang et al., 2003; Sirotkin et al., 2003). Due to its stimulatory action on ovarian functions in animals (Jiang et al., 2003; Mihm and Ervans, 2008) and humans (Vegetti and Alagna, 2006), it is widely used for induction of ovulation, embryo production and assisted reproduction. On the other hand, mutations is FSH receptor could induce premature ovarian failure in humans (Suzumori et al., 2007). 3.3.2.2. LH Results of LH treatment and studies of consequences of polymorphism and mutations in LH receptors demonstrated an important role of LH in

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control of different reproductive processes. LH receptor inactivation don‟t affects pubertal maturation, but induces hypoestrogenism and infertility. Antral follicles don‟t reach preovulatory stage, but form ovarian cysts suggesting the importance of LH in control of late stages of folliculogenesis, estrogen release and ovulation (Huhtaniemi, 2004). LH deficiency in knockout mice inhibited development of follicular granulosa (but but not theca layer), corpus luteum, steroid hormone release (Kumar, 2007). In the gonadotrophin-dependent phase of follicular development, LH also seems to acts within a critical window of the hormone concentration framed between the minimal threshold and a ceiling for the normal functions of the follicle unit. (Palermo, 2007). Furthermore, LH is considered as main promoter of ovulation, luteinisation and corpus luteum development (Berisha and Schams, 2005; Webb and Campbell, 2007). In contrast to FSH, LH appears to stop ovarian cell proliferation and induce their resistance to apoptosis probably via induction of progesterone receptors (Quirk et al., 2004). In cultured ovarian cells, LH treatment was able to stimulate progesterone, estradiol, oxytocin, vasopressin, IGF-I, cAMP, cGMP and oocyte maturation (Sirotkin et al., 2003, 2009b). Due to its stimulatory action on preovulatory ovarian follicle, LH is used in some new stimulation protocols, combining recombinant FSH, recombinant LH and GnRH antagonists to induce oocyte maturation, ovulation and to treate human infertility (Vegetti and Alagna, 2006). State and mutation in LH/hCG receptors can be responsible for development of premature ovarian failure (Suzumori et al., 2007).

3.3.3. Steroid hormones Produced de novo from cholesterol, steroid hormones progestins, androgens and estrogens are synthesised by the ovary in a sequential manner, with each serving as substrate for the subsequent steroid in the pathway. The two-cell, two-gonadotrophin model describes the role of theca and granulosa cells in the production of steroids, highlighting the cooperation between the two cell types, which is necessary for estrogen production According to this model, in the theca, under the influence of LH, cholesterol is converted to pregnenolone and metabolised through a series of substrates ending in androgen production. Androgens produced by the theca cells transported to the granulosa cells where they are aromatised to estrogens under influence of

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FSH. Analysis of consequences of treatmen with steroid receptors blockers and knock-out animals with deficit of these receptors enabled to understand physiological functions and interrelationships between various steroid hormones and other ovarian regulators, which are described more detailed in special reviews (Kolibianakis et al., 2005; Drummond, 2006; Peluso, 2007; Sondheimer, 2008) 3.3.3.1. Progestins Progesterone receptors (classical cytoplasmic receptors, forms A and B, the membrane progesterone receptors MPRalpha, beta, and gamma and a progesterone binding protein referred to as progesterone receptor membrane component-1, PGRMC1) are localised to theca of small, large and preovulatory antral follicles and granulosa cells and in corpora lutea. Progesterone can inhibit mitosis of granulosa cells, transition of primordial follicles to primary follicle, suppress apoptosis in granulosa cells. Progesterone is necessary for induction of ovulation of Graafian follicle by two ways: induction of preovulatory LH surge and promotion the production of proteolytic enzymes important for the rupture of follicles at ovulation, either directly, or by enhancing endometrial relaxin production , which is thought to stimulate the release of proteases by granulosa cells. Previosly it was accepted, that progesterone is not involved in promotion of pre- and post-ovulatory luteinisation of ovarian follicles and Corpus luteum development, if it is formed after ovulation. On the othert hand, presence of progesterone receptors in corpus luteum, as well as the ability of progesterone to regulate a gene cascade that is essential for the transformation of granulosa cells into fully functional luteal, to maintains the integrity of the luteal cells by inhibiting its apoptosis and enhance the activity of steroidogenic enzymes and its own production and to inhibit estradil release by granulosa and luteal cells (endocrine markers of luteinisation) suggest, that progestins are promoters of ovarian follicle luteinisation and corpus luteum development and maintenance (Drummond, 2006; Peluso, 2007). Furthermore, progesterone receptors are involved in signal cascade, that increases survival and prevents apoptosis in granulosa-lutein cells (Peluso et al., 2009), corpus luteum and ovarian cancer cells (Peluso, 2007). Progesterone is a major regulator of the process of ovulation. Female mice lacking progesterone receptor exhibit an anovulatory phenotype due to failure in follicular rupture (Kim et al., 2009). Progesterone is able to stimulate release of GH from anterior pituitary (Kooistra and Okkens, 2001), as well as production of their derivates testosterone and estradiol, oxytocin, IGF-I, IGFBP-3, cAMP, cGMP by ovarian cells (Sirotkin

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et al., 2003). In some species progesterone is a known promoter of oocyte maturation (Deng et al., 2009). Progestagens produced by ovarian follicles and corpora lutea are controlling a number of reproductive events not only within the ovary (see above), but out of it: controls gonadotropin surge, inhibits proliferation and stimulates decidualization the endometrial bed and subsequent embryo implantation a.o. Therefore, their chemical analogues are used as the main current contraceptives, whose suppress mid-cycle surge of LH, ovulation and embryo implantation (Sondheimer, 2008). 3.3.3.2. Androgens Androgens, primarily androstenedione and testosterone, are produced by theca cells in response to LH. Androgens act via their cytoplasmic receptors localised to granulosa cells, including cumulus oophorus, stromal cells, theca cells and oocytes in preantral and antral ovarian follicles. The wide array of androgen effects on ovarian functions are reported (see review of Drummond, 2006). Androgens are promoting proliferation of follicular cells, recruitment and development of ovarian follicles up to preovulatory stage, either stimulate or suppress development of Graafian follicles and their ovulation, increase apoptosis and follicular atresia at different stages of follicullogenesis and promotes oocyte nuclear maturation. Testosterone treatments altered release of progesterone, estradiol, oxytocin, IGF-I, IGFBP-3, prolactin-like substance and cyclic nucleotides by cultured ovarian cells (Sirotkin et al., 2003). Furthermore, they increase the number of FSH and IGF-I receptors in primary and periovulatory follicles and the response of follicles to these hormones. In contrast to FSH receptors, androgens are reported to inhibit FSH-stimulated LH receptor expression by granulosa cells, which could explain the inhibitory action of androgens on late, LH-dependent, stages of follicullogenesis (Drummond, 2006). Genetic studies revealed, that androgen receptors are necessary for ovarian follicle health, development, ovulation, age-related changes in female fertility, although these studies don„t always enable to distinguish the action of androgen at the hypothalamic-pituitary axis and on the ovary (Walters et al., 2008). Direct treatment of follicles with antiandrogenic compounds is able to reduce follicular growth during the preantral phase, alter steroidogenic environment, and arrest oocyte meiotic maturation in response to human chorionic gonadotropin (Lenie and Schmitz, 2009). Other in-vitro studies demonstrated, that androgens can be direct promoters of ovarian follicullogenesis, reception of gonadotropins, ovarian cell proliferation, follicular atresia, oocyte

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maruration, ovulation, corpus luteum development and fecundity (Walters et al., 2008, Fig.2).

Figure 2. Androgen actions and presence of androgen receptor expression during different stages of ovarian follicular development (from Walters et al., 2008).

Hyperproduction of androgens or high androgen/estrogen rate induces appearance of large polyfollicular ovaries and polycystic ovarian syndrome (PCOS). In humans, hyperandrogenism is a classic symptom of PCOS. It is thought that the theca cells of PCOS ovaries are not responsive to downregulation by gonadotrophins allowing for unchecked androgen hyperproduction. Antiandrogens can restore ovultion and fecundity in PCOS patients (Drummond, 2006) and increase ovulation rate and litter size in pigs (Pope and Cardenas, 2006), but reduce ovulation rate and fertility in rats. On

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the other hand, the knockout mouse, which lack functional androgen receptors, but are fertile, indicate that androgen receptors are not essential for mice fertility (Drummond, 2006; Walters et al., 2008). Therefore, androgens could be practically used for regulation of fecundity and treatment reproductive disorders, although their effects can vary in depends of species and reproductive state. Some effects of androgens are primary, others are due to aromatization of androgens to estrogens, whose role in control of ovarian functions is very important too. 3.3.3.3. Estrogens Estrogens signal via estrogen receptors (ER) of which there are two forms, ERα and ERβ, with ERβ being the predominant form in the ovary. Distinct roles for each receptor were identified: ERα inhibited ovulation, most likely via an effect on the hypothalamo-pituitary axis and uterine growth; while ERβ stimulated follicular growth, decreased atresia, induced the expression of specific genes and enhanced the number of oocytes released following ovulation induction. Estrogens are able to stimulate proliferation of granulosa cells, growth and differentiation of antral ovarian follicles (especially at later stages of their development) and reduced follicle atresia. Ocurrence of estrogens and their receptors is necessary for maintaining ovarian cycle, ovarian follicle selection, oocyte growth and maturation, ovulation, formation of corpus luteum and fertility. An important role of different steroid hormones receptors in triggering nuclear maturation of oocytes has been demonstrated (Deng et al., 2009). In addition, estrogens are potent regulators of ovarian hormones release: thir influence on output of gonadal GnRH-I and GnRH-I receptors (Leung and Cheng, 2004), progesterone, oxytocin, IGF-I, IGFBP-3, prostaglandins F and E, prolactin-like substance, cAMP and cGMP are reported (Sirotkin et al., 2003). Furthermore, estrogens are able to suppress FSH and LH release, promote formation of receptors to FSH, LH and prolactin, as well as post-receptory intracellular mediators of hormones action - cAMP, cAMP binding sites, phosphatidylinositol 3-kinase (PI3K)/phosphatidylinositol- dependent kinase 1 (PDK1), glucocorticoid-induced kinase (Sgk) and protein kinase B (PKB or Akt), transcription factor forkhead homologue of rhabdomysarcoma (FKHR) a.o. (Sirotkin et al., 2003; Kolibianakis et al., 2005; Drummond, 2006). Since only healthy follicles, whose are able to grow and ovulate in response to gonadotropins are able to produce large amount of estrogens (see

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below), the estrogen profile could be used for prediction of success of induced ovulation and in vitro fertilisation outcome (Broekmans et al., 2006). On the other hand, abnormal formation of steroids and their receptors can be cause of somer disorders like premature ovarian failure, PCOS, infertility, ovarian cancer a.o., whose could be treated by estrogen aginists or antagonists (Rebar, 2009; Santen et al, 2009). For example, estrogen receptor overexpression can be cause of estrogen-dependent ovarian cancer, which could be prevented or treated (in combination with other treatments) with estrogen receptor or aromatase blockers (Li et al., 2008; Santen et al., 2009). ErbB receptor overexpression has been correlated with poor prognosis and decreased therapeutic responsiveness in ovarian cancer patients. Thus, anticancer agents targeting ErbB/EGF receptors hold great promise for personalized cancer treatment. Yet, challenges remain in designing prospective clinical trials to assess the clinical utility of ErbB receptors and their ligands to diagnose cancer; to predict progression-free and overall survival, therapeutic responsiveness, and disease recurrence; and to monitor treatment responsiveness (Lafky et al., 2008). In addition, steroid hormones, produced by ovarian follicles, Corpus luteum, brain and other tissues have numerous actions outside the ovary. They promote the development and function of other reproduction-related cells, tissues and organs including the oviduct and uterus, and they maintain secondary sexual features of phenotype including those in the brain responsible for sexual behavior. Estrogens and androgens are also essential for many physiological processes not directly related to reproduction, such as cell proliferation and growth and differentiation of a variety of non-ovarian tissues, development of muscles, bone formation, the elasticity of skin tissue and aspects of mental health. Many of these extra-ovarian steroid effects involve interactions with other parts of the endocrine, nervous and other systems. Therefore, inadequate steroid release could result not only ovarian disorders mentioned above, but also disorders in other systems like non-ovarian cancer, osteoporosis, insufficient myogenesis, atypical sexual behavior a.o. (Li et al., 2008; Rebar, 2009; Santen et al, 2009).

3.4.4. Growth Hormone (GH) This hormone is produced by anterior pituitary, leukocytes, uterus, placenta and other tissues. Receptors for GH are present in both follicular somatic cells and in the oocytes. GH is promoter of preantral follicle growth

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and development of small antral follicles to gonadotrophin-dependent stages. Furthermore, GH can promote ovarian cell proliferation and ovarian follicullogenesis and luteogenesis, inhibit their apoptosis, control release of progesterone, prostaglandin, oxytocin, cAMP and cGMP, duration and rate of oocyte maturation, pregnancy and number of pups. Example of direct action of GH on secretory activity of human ovarian granulosa cells is shown in Fig.3. Furthermore, GH can alter formation of gonadotropin receptors and promote effects of gonadotropins on ovarian follicular growth, ovulation and conception rate. GH can affect ovarian cell through its own receptors or via stimulation of IGF-I or oxytocin. The ability of GH to promote reproductive processes and the effects of gonadotropins is used for application of GH, together with gonadotropins or IGF-I, to treat hypogonadotropic hypogonadism or polycystic ovarian syndrome (PCOS) (Sirotkin et al., 2001, 2003, Sirotkin, 2005; Lucy, 2008; Silva et al., 2009). Furthermore, involvement of GH in mediating malnutrition-induced postpartum anestrus in farm animals (Lucy, 2008) suggest potential usefulness of GH for characterisation and prediction of this ovarian disorder.

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3.4.5. Prolactin Is produced in a number of tissues including ovarian granulosa cells (Sirotkin et al., 1994). The receptors to prolactin in the ovary have not been demonstrated, but prolactin can affect ovarian functions via receptors to structurally similar GH. Prolactin was reported to affect release of progesterone, estradiol, oxytocin, vasopressin, cAMP and cGMP by cultured granulosa cells (Sirotkin et al., 2003), as well as the number of marophages, regulating state and promoting lysis of corpus luteum (Kucharski and Jana, 2005). The involvement of prolactin in control of fecundity is not demonstrated yet, although it can be involved in so called lactational infertility during suckling, which is associated with increased prolactin release (McNeilly, 1997). Despite the temporal association of high prolaction release with ovarian inactivity and the influence of prolactin on ovarian functions listed above, no association between polymorphysm in prolactin genes and pig fertility rate was found (Kątska-Książkiewicz et al., 2006; KorwinKossakowska et al., 2009). Plasma prolactin level can be predictive marker of development of ovarian cancer and its sensitivity to chemotherapy (Kim et al., 2009).

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Figure 3. Effect of GH additions on the release of progesterone, estradiol (a), oxytocin (OT), insulin-like growth factor 3 (IGFBP-3) (b), cAMP and cGMP (c) by cultured human granulosa cells (from Schaeffer and Sirotkin, unpublished; Sirotkin, 2005).

3.4.6. Oxytocin and its Analogues This nonapeptide hormone, like its analogues vasopressin, argininevasotocin, mesotocin, isotocin a.o. are produced by magnocellular hypothalamic nuclei and stored in posterior pituitary. Besides hypothalamus, oxytocin and, probably, other nonapeptide hormones are produced by granulosa cells of ovarian follicles, especially after their luteinisation under influence of gonadotropins, IGF-I and other hormonal stimulators. The majority of oxytocin presented in ruminant‟s blood is of ovarian origin. In

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addition, oxytocin could be produced by placenta and some other tissues. Receptors to oxytocin are present in ovarian follicles, corpus luteum, oviduct, uterus and other reproductive organs (Gimpl and Fahrenholz, 2001). Oxytocin is able to stimulate follicular growth in vitro, granulosa cell proliferation, release of progestagen, androgen, estrogen, IGF-I, inhibin A, prostaglandins F and E, cAMP and cGMP (but not IGFBP-3), whilst immunoneutralisation of oxytocin inhibited secretory activity of ovarian cells (Sirotkin et al., 2001, 2003). During corpus luteum development, oxytocin promotes proliferation and luteinisation/progesterone release by luteal cells (Berisha and Schams, 2005; Niswender et al., 2007; Skarzynski et al., 2008). During luteolysis, oxytocin as luteotropic hormone can oppose the luteolytic action of prostaglandin F2 alpha (Gimpl and Fahrenholz, 2001). On the other hand, the presence of uterine oxytocin receptors are important for the luteolytic effect of PGF2alpha (Ziecik et al., 2006). Therefore, the exact role of oxytocin in luteolysis remain to be studied. Vasopressin and arginine-vasotocin was able to inhibit progesterone and to stimulate estradiol and cAMP release by ovarian cells. No effect of oxytocin and vasopressin on oocyte nuclear maturation was found, although argininevasotocin was able to promote it (Sirotkin et al., 2003).

3.4.7. Leptin Leptin, a product of adipose and some other tissues, which production is prmoted by food intake, can be an important hormone through which metabolic and nutritional factors (mainly food consumption) affect reproductive processes. Leptin can affect reproduction through the hypothalamo-hypophysial system and by direct action on gonads, but available information concerning both leptin effects remains unclear. Regarding the effects of leptin at CNS level, some reports demonstrated a stimulatory influence of leptin on hypothalamic GnRH and hypophysial gonadotropin production (Munoz-Gutierrez et al. 2005; Zieba et al., 2005; Klock et al., 2007). Regarding direct effects on the ovary, leptin, via ovarian leptin receptors (Zerani et al., 2004), was found to stimulate growth of ovarian follicles (Munoz-Gutierrez et al, 2005). It was shown to be direct inhibitor (Zerani et al., 2004; Tsai et al., 2006) or stimulator (Gregoraszczuk and Ptak, 2005) of corpus luteum development and maintenance, and promoter of oocyte nuclear and cytoplasmic maturation (Craig et al., 2004).

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Figure 4. Leptin injections some affectreproductive plasma level of progesterone (a),rabbits. estradiol (b), estroneparameters (e) in female C- control, Lsulphate (c), IGF-I (d) and reproductive parameters (e) in female rabbits. C- control, leptin administration. (fromsome Sirotkin et al., 2009b) L-leptin administration. (from Sirotkin et al., 2009b).

Leptin inhibited porcine (Gregoraszczuk and Ptak, 2005; Sirotkin and Meszarošová, 2010) ovarian cell apoptosis, but in human granulosa cells leptin promoted it (Sirotkin et al., 2008b). Leptin treatment activated human and porcine ovarian cell proliferation (Sirotkin et al., 2007; Sirotkin and

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Meszarošová, 2010). Leptin can also affect (mainly stimulate) ovarian steroidogenesis, oxytocin, prostaglandins, IGF-I and IGFBP-3 release (Zerani et al., 2004; Munoz-Gutierrez et al, 2005; Tsai et al., 2006; Sirotkin and Grossmann, 2007; Sirotkin et al., 2005, 2009b; Sirotkin and Meszarošová, 2010). Moreover, just IGF-I can be local mediator of leptin action on ovarian cells (Sirotkin et al., 2005). Both stimulatory (Kun et al., 2007) and inhibitory (Sirotkin and Bezakova, unpublished) effect of leptin on oocyte nuclear maturation has been detected. Finally, leptin treatments were able to increase rabbit fertility (Sirotkin et al., 2009b). The ability of leptin administration to alter plasma hormone level and to improve reproductive parameters in rabbits is demonstrated by Fig. 4. Taken together, the available data suggest, that leptin can be potent stimulator of reproductive processes at both hypothalamohypophysial and ovarian level and one of important mediator of effect of optimal nutritional conditions on reproductive processes (Mircea et al., 2007; Pinelli and Tagliabue, 2007). Serum leptin level can be used to characterise and predict metabolismrelated reproductive disorders like aberrant puberty and ovarian cycle, infertility induced by anorexia nervosa, exercise-induced amenorrhoea and obesity, PCOS (Mircea et al., 2007; Pinelli and Tagliabue, 2007), development of ovarian cancer and its sensitivity to chemotherapy (Kim et al., 2009b).

3.4.8. Ghrelin Ghrelin, a peptide hormone produced by stomach and other tissues, is a known promoter of food intake, adiposity and other metabolism-related processes, of hypophysial secretion of GH and, to a lesser extent, of prolactin, ACTH and vasopressin (van der Lely et al., 2004; Klok et al., 2007). Like leptin, it can be mediator of effect of nutrition on a number of metabolismrelated processes, although, in contrast to leptin, it mediates rather effects of insufficient calories intake. As concernes reproduction, ghrelin can suppress the secretion of hypothalamic LH-RH and hypophysial gonadotropins (Garcia et al., 2007). By direct action on the ovary, ghrelin was able to promote ovarian cell proliferation (Sirotkin et al., 2006; Sirotkin and Grossmann, 2007; Sirotkin and Meszarošová, 2010). In mammalian ovaries it decreased apoptosis (pig: Sirotkin et al., 2009a, rabbit: Sirotkin et al., 2009b), but in chicken ovaries ghrelin promoted apoptosis (Sirotkin et al., 2006; Sirotkin and Grossmann, 2007). Finally, ghrelin altered release of progesterone, testosterone, estradiol, vasotocin, IGF-I and prostaglandins F and E by animal

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granulosa cells (rabbit: Sirotkin et al., 2009b; pig: Sirotkin et al., 2008, 2009a; Sirotkin and Meszarošová, 2010; chicken: Sirotkin et al., 2006; Sirotkin and Grossmann, 2007), as well as progesterone, prostaglandins F2 alpha, E2 and VEGF release by human lutheal cells (Tropea et al., 2007; Viani et al., 2008). Direct inhibitory action of ghrelin additions to secretory activity of cultured porcine ovarian follicles is shown at Fig. 5. Moreover, ghrelin was able to prevent the effects of LH, IGF-I (rabbit: Sirotkin et al., 2009b) and leptin (human: Sirotkin et al., 2009a) on ovarian cells. These observations suggest, that ghrelin can be antagonist of leptin in regulation of reproductive processes at both hypothalamo-hypophysial and ovarian level and the hormone, which mediates suppressive effect of malnutrition on reproductive processes. b.

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Figure 5. Inhibitory effect of ghrelin addition on release of progesterone (a), testosterone (b), oxytocin (c) and prostaglandin F (d) by cultured porcine ovarian follicles. Data of RIA. (from Sirotkin and Kotwica, unpublished).

Figure 5: Inhibitory effect of ghrelin addition on release of progesterone (a), testosteron (b), oxytocin (c) and prostaglandin F (d) by cultured porcine ovarian follicles. Data of RIA. (from Sirotkin and Kotwica, unpublished) Regulators of Ovarian Functions, Nova Science Publishers, Incorporated, 2014. ProQuest Ebook Central,

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Alexander V. Sirotkin

In addition, ghrelin can activate antioxidant enzyme and suppress lipid peroxidation in ovarian cells (Kheradmand et al., 2010) i.e. potentially support viability and resistence of these cells to oxidative stress and apoptosis. No effect of ghrelin treatments on rabbit fertility was found, although ghrelin administration decreased mortality of pups born (Sirotkin et al., 2009b). Since ghrelin is one of possible mediators of effect of nutrition and metabolism on reproductive processes, it is proposed, that it could be used for detection of metabolism-related ovarian disorders and even for treatment of some reproductive disorders induced by anorexia (Klock et al., 2007; Mircea et al., 2007).

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3.4.9. Obestatin Production of obestatin, a 23-amino acid peptide encoded by the same gene as ghrelin, was demonstrated in different tissues, but not in the ovary. Although ghrelin and obestatin originate from the same precursor prepropeptide, most reports suggest that these hormones have opposing physiological roles. Obestatin, in contrast to ghrelin can decrease food intake, inhibits gastric emptying and contractile activity of the jejunum and decreases weight gain. Obestatin, in contrast to ghrelin, did not alter GH secretion by cultured rat pituitary cells (Zhang et al., 2005; Nogueiras et al., 2006). Obestatin may affect physiological systems by both CNS and peripheral structures. The estrous cycle – dependent changes in obestatin production in mice was the first indirect evidence for its involvement in control of reproduction (Zhang et al., 2005). Recently it was found, that obestatin stimulates proliferation, apoptosis, release of progesterone, but not testosterone or estradiol by cultured porcine granulosa cells (Mészárosová et al., 2008). The role of obestatin in mediating effect of nutrition on reproduction, in control of reproduction in other species and possible practical application of this novel peptide remain to be studied yet.

3.4.10. Prostaglandins The prostaglandins are members of eikosanoid family - signaling lipid molecules, whose are synthesized from 20-carbon polyunsaturated fatty acids

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(mainly arachidonic acid) in every cell type in the body. This large family consists on prostacyclins, tromboxanes, leukotrienes and lipoxins, whose differ by their structure and action. Prostaglandins act as paracrine, autorcrine and endocrine signaling substances. In the ovary prostaglandins synthesis and secretion was demonstrated in both granulosa and theca interna cells. The most important direct stimulators of these process are GnRH, LH, hCG, GH, oxytocin, some growth factors (IGF-I, GDF-9, TGF alpha, FGF) and their binding protein (IGFBP-3) (see below) (Sirotkin et al., 2002, 2003; Sirois et al., 2004), leptin (Sirotkin et al., 2005, 2009b) and ghrelin (Benčo et al., 2009; Sirotkin et al., 2009c). Prostaglandins are involved in control of reproduction at the level of the pituitary, ovary, uterus, placenta. They play an important role in maternal recognition of pregnancy, implantation, maintenance of gestation, microbial-induced abortion, parturition, postpartum uterine and ovarian infections, and resumption of postpartum ovarian cyclicity (Weems et al., 2006). As concernes the ovary, prostaglandins regulate a number of genes in ovarian follicle (Stouffer et al., 2007). Prostaglandin F and E receptors were detected in ovarian follicles in different species, whilst they formation increased in periovulatory period. This suggests, that prostaglandins are not involved very much in control of ovarian folliculogenesis, but rather to ovulatory and post-ovulatory events. Inactivation of prostaglandin E and F receptors results impaired ovulation, cumulus expansion, oocyte competence to fertilization (Sirois et al., 2004). In the ovary, the most known functions of prostaglandins are control of ovulation, luteogenesis, luteolysis and stimulation of oocyte maturation and cumulus oophorus expansion (Sirois et al., 2004; Weems et al., 2006), although other studies demonstrated, that PGE (at least in primates) is essential for release of the oocyte; but not necessarily for follicle rupture, and not for luteinization (Stouffer et al., 2007). During Corpus luteum development, prostaglandin F2 alpha can increase number of both small and large luteal cells (Niswender et al., 2007). On the contrary, in the second half of luteal cycle, prostaglandin F2 alpha is potent luteolytic agens. Prostaglandin E2 and prostacyclin is considered as luteotropic. Moreover, prostaglandin E2 can protect corpus luteum from the luteilytic effect of prostaglandin F2 alpha. Prostaglandin E/prostaglandin F rate, together with gonadotropins and local growth factors determine function and terms of maintenance of corpus luteum (Sirois et al., 2004; Berisha and Schams, 2005; Ziecek et al., 2006; Skarzynski et al., 2008). Although stimulatory effect of prostaglandin F2 alpha on MAP kinase involved in promotion of ovarian cell proliferation and prevention of apoptosis has been reported (Tai et al., 2001), no direct evidence for involvement of prostaglandins in control of ovarian

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Alexander V. Sirotkin

follicular or luteal cell proliferation and death are available yet (Sirois et al., 2004). Furthermore, although prostaglandins are produced by ovarian follicles, no consistent data concerning prostaglandin effects on follicular functions are reported in the recent years. For example, prostaglandin F2 alpha, a known blocker of animal luteal progesterone release (Berisha and Schams, 2005; Ziecek et al., 2006; Skarzynski et al., 2008), was reported to inhibit progesterone release by luteinised human granulosa cells (Abayasekara et al., 1993), but this effect was not confirmed by other studies (Väänänen et al., 1997). Although many aspects of prostaglandin action remain unknown yet, prostaglandins are practically used to synchronize estrus, terminate pseudopregnancy in mares, induce parturition, and treat retained placenta, luteinized cysts, pyometra, and chronic endometritis (Weems et al., 2006).

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3.4.11. Indoleamines serotonin and melatonin Serotonin and melatonin are indoleamines, product of aminoacid tryptophan. Serotonin is a neurotransmitter, hormone and growth factor produced by gut, nervous system, mast cells, leukocytes and a number of other cells. Melatonin is produced by pinal, retina, gut and probably some other cells from serotonin. Therefore, some described effects of serotonin could be explained by its local conversion to melatonin. Serotonin (or 5- hydroxytryptamine, 5-HT), its producing enzyme, transporter and specific receptors, 5-HT(1D), 5-HT(2A-B) and 5-HT(7)), were detected in ovarian granulosa cells, cumulus oophorus and oocytes (Dubé and Amireault, 2007). Mouse mothers with knocked-out serotonin receptor (5HT 1D) were fertile, although impaired embryogenesis occured (Dubé and Amireault, 2007). In cultured porcine granulosa cells, serotonin stimulated oxytocin and cGMP production and inhibited vasopressin and cAMP production. In cultured human granulosa cells it increased IGF-I, decreased oxytocin, progesterone and estradiol release (Sirotkin et al., 2003) and modify effect of LH on progesterone output (Koppan et al., 2004) . In addition, serotonin can control cAMP and progesterone production by cumulus oophorus (Dubé and Amireault, 2007) and modify effect of LH on oocyte developmental competence (Patiño et al., 2001). The production of melatonin (Finocchiaro and Glickin, 1998) and its receptors (Leung and Cheng, 2004; Tamura et al., 2009) by ovarian granulosa cells has been demonstrated. In cultured human granulosa cells, melatonin

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inhibited tle expression of GnRH-I and GnRH-I receptors, increased that of LH receptors (Leung and Cheng, 2004). In bovine and porcine granulosa cells it stimulated estradiol and cGMP and reduced progesterone, oxytocin, vasopressin and cAMP production. Furthermore, it promoted reinitiation, but not the completion of nuclear maturation of bovine oocytes (Sirotkin et al., 2003). In cultured murine ovaries, melatonin additions promoted progesterone and androstenedione, but not estradiol release and reduced oocyte maturational capacity (Adriaens et al., 2006). In different species melatonin administration in vivo was able to promote ovarian growth and folliculogenesis, to induce ovarian cycle and oocyte developmental competence (Ghuman et al., 2008; Berlinguer et al., 2009; Hemadi et al., 2009). In these cases, however, central and peripheric effects of indoleamines is difficult to distinguish. In addition to specific, receptormediated action, melatonin can be receptor-independent free radical scavenger and a broad-spectrum antioxidant supporting viability and resistence of cells to damaging factors (Tamura et al., 2009). Therefore, serotonin and melatonin can be involved in control of a broad range of reproductive processes including ovarian growth, follicullogenesis, release of signalling substance and oocyte maturation. Due to their effects on the ovary, these indoles, especially melatonin, also have potential roles in the pathophysiology and possible treatment of anoestrus (Ghuman et al., 2009), endometriosis, PCOS, and premature ovarian failure (POF) (Tamura et al., 2009), as well as in improvement of ovarian transplantation technique (Hemadi et al., 2009).

3.4.12. Insulin-like growth factors (IGFs) The insulin-like growth factors (IGFs) are polypeptides with high sequence similarity to insulin. The IGFs-related signalling system consists of two receptors (IGF1R and IGF2R), two ligands (IGF-1 and IGF-2), six IGF binding proteins (IGFBP 1-6), as well as associated IGFBP degrading proteases. IGFBPs both inhibit IGF action by preventing binding to the IGF-1 receptor as well as promote IGF action through aiding in delivery to the receptor and increasing IGF half-life by preventing IGF degradation. Both IGF-I and IGF-II are using the same functional IGF1R (IGF2R is not working because it don‟t activate any post-receptor signalling pathways), and state and activity of both IGFs are modulated by the same set of IGFBPs.

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All components of IGF-related signalling systems are produced in a range of tissues including ovarian follicles, corpus luteum and oocyte under stimulatory action of low calories intake, gonadotropins, GH, oxytocin and other hormones. In humans IGF-II is primary IGF, whilst in ruminants and rodents the major role in control of reproductive functions plays IGF-I (Guidice, 2001). The bioavailability of IGFs within the follicle, like other tissues, is regulated by a family of intrafollicular expressed IGF binding proteins (IGFBPs). Facilitation of IGF can be increased through the activity of specific IGFBP proteases, which degrade the IGF/IGFBP complex, resulting in the production of IGFBP fragments, release of attached IGFs and their action on local target ovarian cells (Silva et al., 2009). IGF-I has probably no effects on primordial follicle development, but both IGF-I and IGF-II stimulate growth of secondary follicles in vivo and in vitro. In antral follicles, these IGFs stimulate granulosa cell proliferation and steroidogenesis and inhibit apoptosis (Sirotkin et al., 2003; Webb and Campbell, 2007; Mihm and Evans, 2008; Silva et al., 2009). On the other hand, IGFBPs (especially IGFBP-4) can be inductors and markers of atresia of individual follicles (Webb and Campbell, 2007). Graafian follicles, in copmarison to other follicles contain increased amount of IGF-II and reduced amount of IGFBP-4 (Giudice, 2001). Therefore, IGFs and IGFBPs are important promoters not only of follicular growth, but also of follicular selection. Furthermore, IGFs augment expression of FSH and LH receptors and response of granulosa and theca cells (Natesampillai and Veldhuis, 2004) and oocytes (Patiño et al., 2001) to gonadotropins. Moreover, IGFs are considered as main local mediators of gonadotropin action in the ovary (Guidice, 2001). Therefore, gonadotropins and IGFs represent the self-stimulating system activating ovarian follicular functions. IGF-I can be mediator of GH (Sirotkin et al., 2001, 2005), oxytocin (Sirotkin et al., 2001) and leptin (Sirotkin et al., 2005) action on ovarian cells too. IGF-I and IGF-II produced at high amounts in corpus luteum, can support luteal development and functions up to mid-luteal stage, but direct evidence for this hypothesis are absent now (Berisha and Schams, 2005). High expression of IGFBP-4 during pregnancy (Guidice, 2001) could be related to involvement of this IGFBP in maintenance of corpus luteum function. IGF-I and –II are potent regulators (mainly promoters) of ovarian secretory activity: they stimulate release of progesterone, testosterone, estradiol, oxytocin, IGFBP-3, inhibin A, cAMP, cGMP, prostaglandins F and E in ovarian cells of different mammals and chicken, as well as stimulated

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(IGF-II) or inhibited (IGF-I) arginine-vasotocin release by chicken ovarian cells. Furthermore, IGFBP-3 and IGFBP-4 can be potent regulators of not only IGFs, but also progesterone, oxytocin, prostaglandins F and E and other IGFBPs (Hernandez et al., 1998; Sirotkin et al., 2003, 2009b). Both IGF-I and IGF-II promoted nuclear maturation of oocytes; they also stimulated proliferation and inhibited apoptosis in the surrounding cumulus oophorus, increased developmental competence of oocytes and promoted early embryogenesis (Patiño et al., 2001; Sirotkin et al., 2003; Hunter, 2004; Velazquez et al., 2009). It is possible, that IGF-I and IGF-II can mediate effect of nutrition and nutrition-dependent metabolic hormones on reproductive processes (Hunter et al., 2004; Sirotkin et al., 2005; Lucy, 2008). Circulating or local IGFs and their IGFBPs could be practically used for characterisation of postpartum anestrus in farm animals (Lucy, 2008), prediction of reproductive success and for selection of animals with high fertility (Kątska-Książkiewicz et al., 2006) and for prediction of in-vitro fertility outcome in normal patients and patients suffering from PCOS (Schoyer et al., 2007) or ovarian cancer (Kim et al., 2009). IGFs treatments are contemporarily used for stimulation of in-vitro oocyte maturation and embryo production (Velazquez et al., 2009). On the other hand, blockers of IGF1R could be used for inhibition proliferation of ovarian cancer cells (Gotlieb et al., 2006).

3.4.13. Epidermal Growth Factors (EGFs) Epidermal growth factor (EGF) is a protein with 53 amino acid residues and three intramolecular disulfide bonds. It is the founding member of the EGF-family. Members of this protein family have highly similar structural and functional characteristics. Besides EGF itself other family members include: heparin-binding (HB-EGF), transforming growth factor (TGF-α), amphiregulin (AR), epiregulin (EPR),epigen, betacellulin (BTC) and neuregulins-1-4 (NRGs 1-4). These substances affect target cells through four types of structurally-related transmembrane receptors (Lafky et al., 2008). Recent literature demonstrates involvement of both EGF and such EGFlike growth factors as amphiregulin, epiregulin, and betacellulin in control of ovarian functions. Production of these factors and their receptors (EGFRs) by rodent‟s and human follicular granulosa cells, which is dramatically increases under influence of GnRH (Motola et al., 2006) and preovulatory LH surge

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(Panigone et al., 2008) in periovulatory period was reported. This indicates involvement of EGF network in control of ovulation-related events and in mediating GnRH and gonadotrpin effect on the ovary (Conti et al., 2006; BenAmi et al., 2006; Hsieh et al., 2009). EGF stimulates proliferation of ovarian granulosa cells, increases release of progesterone, cAMP, cGMP and controls release of estradiol. Furthermore, it stimulates oocyte maturation, proliferation of cumulus oophorus cells and inhibits their apoptosis (Sirotkin et al., 2003). Perturbation of EGF-like growth factors amphiregulin, epiregulin, and betacellulin (Conti et al., 2006; Hsieh et al., 2009), their receptors (Panigone et al., 2008) or their post-receptor EGFR protein kinase (Motola et al., 2006) impairs rodent‟s ovulation. Besides ovulation, these growth factors are potent stimulators of oocyte maturation and cumulus expansion, which, probably, mediates influence of EGF-like growth factors on oocytes (Ben-Ami et al., 2006; Conti et al., 2006; Hsieh et al., 2009). Influence of EGF-like growth factors on ovarian cell proliferation and apoptosis has not been reported yet, although hCG-induced increase in expression of EGFR, amphiregulin, epiregulin and betacellulin was associated with incresed proliferation of granulosa cells isolated from monkey‟s varian follicles (Fru et al., 2009). Practical application of EGF and EGF-like growth factors is possible. Polymorphysm in EGF gene was associated with fertility rate in pigs (KątskaKsiążkiewicz et al., 2006). Neverttheless, in humans no strong association between EGF levels in the follicular fluid with the state of follicle and oocyte maturation has been found. Therefore, it remains still to be determined, whether it can be used as a biological marker of follicle development (Hsieh et al., 2009). Nevertheless, its application for improvement of in-vitro oocyte maturation is possible. The EGFR are considered as proto-oncogenes because they play important physiologic roles in cell proliferation, survival, adhesion, motility, invasion, and angiogenesis in normal and malignant cells, including ovarian tumors. Clinically, the diagnostic, prognostic, and theragnostic significance of any single EGFRs and their ligands is controversial, but generally, EGFR overexpression has been correlated with poor prognosis and decreased therapeutic responsiveness in ovarian cancer patients. Therefore, EGFR and their regulators could be potentially used for diagnosis, prognosis and treatment of ovarian cancer and other ovarian disorders (Lafky et al., 2008; Markman, 2008).

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3.4.14. Vascular Endothelial Growth Factor (VEGF) Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that is mitogen and survival factor for the vascular endothelium, which induces formation of new cappillaries in target organs. Regulation of follicular angiogenesis has been shown to be important for the development of ovulatory follicles and curpus luteum. In the ovary, VEGF and its receptors are produced by theca, granulosa, oocyte, cumulus oophorus and corpus luteum. This production is increased at antral stage of follicullogenesis, especially in preovulatory follicles. Primordial, atretic follicles and degenerating corpora lutea produce no or few VEGF. Production of VEGF and its receptors can be stimulated by gonadotropins, prostaglandin E2 and estrogen, but not progesterone (Geva and Jaffe, 2004; Reisinger et al., 2007). Administration of VEGF has been shown to stimulate pre-antral follicular growth and increase the number of pre-ovulatory follicles. It is proposed, that gonaditripin- and steroid-induced VEGF and VEGF-induced microvascularisation of individual follicles plays an important role in follicle selection (Hunter et al., 2004; Berisha and Schams, 2005). Furthermore, corpus luteum cell death was associated with decreased local VEGF expression, whilst blockade of VEGF receptors suppressed luteal angiogenesis. These observations indicated possible involvement of VEGF in maintenance of curpus luteum (Geva and Jaffe, 2004; Skarzynski et al., 2008). Manipulation of the angiogenic process may also provide new opportunities for regulating the quality and number of follicles that ovulate in embryo production in biotechnology and assisted reproduction (Hunter et al., 2004; Berisha and Schams, 2005). Furthermore, womens with PCOS, ovarian hyperstimulating syndrome and ovarian tumors have increased VEGF expression in ovaries. On the other hand, VEGF blockers can inhibit ovarian cancerogenesis. Therefore, VEGF and its receptors could be useful for prediction and treatment of some ovarian illnesses (Geva and Jaffe, 2004; Markman, 2008; Gómez-Raposo et al., 2009). Recently a second family of vascular growth factors, angiopoetins, has been discovered. Angiopoetins promote development of capillaries initiated by VEGF. They are produced in the ovary. Indirect evidence suggest, that angiopoetins can stimulate invasion of capillaries to preovulatory follicle and growing corpus luteum, but the conclusive data concerning their biological role in the ovary are absent yet (Gena and Jaffe, 2004).

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TPO stimulates the expression of some signalling molecules in porcine ovarian follicles PCNA -36K Bax -23K

CDK -34K TK

-48K

PKA -47K CREB-43K

TPO dose (ng/ml)

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0

1

10

100 ng/ml

Figure 6. Effect of thrombopoietin (TPO) on expression of marker of proliferation (PCNA), apoptosis (Bax), protein kinases (cyclin-dependent protein kinase Cdc2/p34, tyrosine kinase/phosphotyrosine TK, protein kinase A, PKA) and transcription factor CREB-1 identified using SDS-PAGE and Western immunoblotting in the lysate of porcine ovarian follicles cultured for 2 days in a serum-free medium. kDa - approximate molecular mass of fractions (from Sirotkin et al., 2004).

3.4.15. Thrombopoietin (TPO) Thrombopoietin (TPO) is a glycoprotein hormone/growth factor produced by different organs (mainly by the liver and the kidney) that regulates the production and differentiation of megakaryocytes in the bone marrow into blood platelets (Kaushansky, 2006). Production of TPO by human (Furuhashi et al., 1999) and hamster (Kaszubska et al., 200; Ryll al.,. 2000) ovarian cells has been demonstrated.. In cultured ovarian follicles and granulosa cells, TPO additions promoted proliferation, apoptosis, release of oxytocin, inhibin A, inhibin B, IGF-I and inhibited androstenedione, estradiol, TGF-2 beta and IGFBP-3, but not progesterone secretion (Sirotkin et al., 2004). Fig. 6 demonstrates influence of TPO additions on the expression of some markers of

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proliferation, apoptosis and some related protein kinases and transcription factor in cultured ovarian follicles. The present observations suggest the involvement of this growth factor in control of basic ovarian functions (proliferation, apoptosis, secretory activity) and its interrelationships with other hormones (steroids, nonapeptides), cytokines and growth factors (inhibins, IGF/IGFBPs, TGF beta). Furthermore, they suggest, that TPO can be practically used not only for recovery of platelet counts after myelosuppressive chemotherapy (Kaushansky, 2006), but also for control of ovarian functions.

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3.4.16. Erytropoietin (EPO) Erytropoietin (EPO, hematopoietin, hemopoietin) is a glycoprotein hormone that promotes erythropoiesis (red blood cell) production in the bone marrow. Expression of EPO and its receptors in ovarian cells has been reported (Paragh et al., 2009). Exogenous EPO did not affect ovarian cell proliferation (Paragh et al., 2009) and androgen production (Hernandez et al., 1998), but inhibited their apoptosis (Solar et al., 2008). Although recombinant EPO has revolutionized the treatment of anemia, recent clinical trials suggested that its use may be associated with decreased survival in cancer patients probably via inhibition of apoptosis (Solar et al., 2008). Furthermore, blockade of EPO receptors was able to inhibit ovarian tumorgenesis and invasivity of ovarian carcinoma cells (Paragh et al., 2009)

3.4.17. Hepatocyte Growth Factor (HGF) The hepatocyte growth factor (HGF) system comprises HGF, its receptor (the c-met tyrosine kinase), HGF activator (HGFA) protein, and HGFA inhibitor (HAI), whose are expressed in the ovary, and whose enables direct and feedback paracrine and autocrine regulation of HGF production and effects. HGF controls numerous key functions which collectively regulate the growth and differentiation of ovarian follicles; these include cell growth, steroidogenesis, and apoptosis within theca and/or granulosa cells (Zachow and Uzumcu, 2007).

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3.4.18. Growth Factors of Hedgehog, Wnt, and Notch Families Recent studies demonstrated the importance of Hedgehog, Wnt, and Notch families of growth factors. Growth factors of Hedgehog and Wnt families, like IGFs, are produced mainly by ovarian somatic cells. Members of Notch family are generated by both follicular cells and oocytes (Pangas, 2008). Hedgehog protein is stimulating proliferation and steroidogenesis in theca cells (Spicer et al., 2009), oocyte maturation (Nguyen et al., 2009), but no effect of Hedgehog regulators on ovarian follicullogenesis was found (Pangas, 2007). Changes in Wnt growth factors during embryonal ovarian development, adult ovarian follicullogenesis, ovulation and corpus luteum development provide indirect evidence for involvement of these molecules in control of these processes. Furthermore, mices deficient for Wnt receptors had normal follicullogenesis and ovulations, but no normal corpus luteum development and embryo implantation suggesting the importance of Wnt signaling pathway in control of luteogenesis and related maintenance of pregnancy and fertility (Pangas, 2007). Ovarian folliculogenesis-related changes in expression of Notch signaling pathway and ability of modulators of this pathway to induce abnormal follicle development and defect in oocyte meiosis, promote follicle luteinisation and impair fertility. These observations suggest the importance of Notch in regulation of ovarian follicullogenesis, oocyte maturation and oogenesis (Pangas, 2007). Wny-related signaling pathway is activated by ovarian cancer, whilst induced activation of this pathway induces granulose cells metaplasia leading to granulosa cell tumor (Pangas, 2007). Expression and production of growth factors of Notch family during cancerogenesis is reported. Notch appears to act as both an oncogene and a tumor suppressor gene depending on the cellular context. It is proposed, that Notch inactivation can be used for targeted treatment of ovarian cancer (Rose, 2009).

3.4.19. Cytokines Cytokines are originally refered as numerous signalling substances that are secreted by certain cells of the immune system which an effect on other cells. The current terminology refers to cytokines as immunomodulating

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agents. Nevertheless, a growing body of evidence demonstrates, that practically all nucleated cells are able to produce cytokines and/or their receptors, that their role is much wider, than only immunomodulatory functions, and there is no strong border between substances refered as cytokines, growth factors and hormones. Cytokines are proteins, peptides, or glycoproteins. The most known cytokines related to reproduction are interleukines (including non-immunological cytokines defined also as growth factors erythropoietin, EPO and thrombopoietin, TPO and transforming growth factors beta, TGF beta), colony stimulating factors (CSFs) and interferons. Among cytokine receptors invovled in control of ovarian functions the most known are tumor necrosis factors (TNFs). There is a number of evidence demonstrating the involvement of member of TGF beta family (activin, inhibin, antimullerian hormone, AMH, bone morphogenetic proteins, BMPs) in control of ovarian functions. Some cytokines involved in control of ovarian functions at the level of pituitary and ovarian cells are listed in Fig. 7. Some growth factors of TGFbeta family (activin, inhibin, antimullerian hormone, AMH, bone morphogenetic protein, BMP 2, BMP4, BMP6) are generated by ovarian follicles, whilst others (BMP6, BMP15 and growth and differentiation factors, GDFs) are secreted by oocytes (Pangas, 2007). Macrophages in the ovary also secrete cytokines, including interferon-g (IFNg), TNF-a and GM-CSF (Ingman and Jones, 2008).

3.4.19.1. Colony stimulating factors (CSFs) Colony stimulating factors (CSFs) are a glycoproteins, whose promote proliferation and differentiation of hemopoetic cells, but whose can be involved in control of reproductive processes. CSF can be produced within ovarian follicles (Salmassi et al., 2010). Mutations of CSF-1 induces dysfunctional LH secretion, reduced ocurrence of antral follicles and ovulation, impaired ovarian luteinization, reduced litter size in mices. These animals were unresponsive to exogenous gonadotropins suggesting that CSF-1 acts locally on ovarian gonadotropin receptors or other gonadotropin-related sites (Ingman and Jones, 2008). Direct action of CSF on ovarian functions are seems not studied yet, although the ability of CSF to promote (Toy et al., 2009) and to prevent (Dou et al., 2009) malignant transformation of ovarian cells has been reported. Circulating CSF level could be used for prediction of in vitro fertilisation outcome (Salmassi et al., 2010).

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Figure 7. Cytokines identified as important in functioning of the hypothalamo-pituitarygonadal axis, and the production of mature gametes (Ingman and Jones, 2008).

3.4.19.2. Tumor Necrosis Factors (TNFs) This family of cytokines consists on Tumor Necrosis Factor (TNF) alpha and beta. TNF alpha is a polypeptide produced by immne and other cells and acting through two types of receptors (TNF-RI and -RII). TNF beta (lymphotoxin) is a homologue of TNF alpha, which production is relatively low, and which involvement in control of reproductive processes has not been revealed yet. Null mutation of TNF and TNF type II receptor (TNFRII) did not affect mouse fertility, but null mutation of TNF type I receptor (TNF-RI) increased prepubertal ovarian responsiveness to gonadotropins, impaired ovarian cycling in aged females (Ingman and Jones, 2008). TNF alpha, its receptor and downstream mediators of their action - TNFalpha-related apoptosis-inducing ligand (TRAIL)-TRAIL receptor (TRAILR), TNF receptor 1-associated death domain protein (TRADD), TNFR-associated factor 2 (TRAF2) produced within ovarian granulosa cells can be physiological inductors of their apoptosis and follicular atresia (Manabe et al., 2008). TNF can promote ovarian cell proliferation. In undifferentiated ovarian cells TNF

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inhibit steroidogenesis, whereas in differentiated ovaries these cytokines stimulate progesterone synthesis (Bornstein et al., 2004). Some ovarian cancer cells secrete increased amounts of TNF, which in turn stimulate their proliferation and invasivity (Bornstein et al., 2004). Therefore, TNF could be predictive index and, maybe, site of treatment of ovarian cancer. 3.4.19.3. Interleukines (ILs) Interleukins (ILs) are polypeptides known best for their production by immunocompetent cells and involvement in the immune system and their role during inflammation. A growing body of evidence suggests that the ovary is a site of both production and action of ILs. Production of ILs and their receptors have been demonstrated in both granulosa and theca cells, whilst maximal production seems occurs in preovulatory follicle after gonadotropin action (Brannstrom, 2004; Ingman and Jones, 2008). Mutations in IL4, IL5, IL9, IL10, IL11, IL13, IL15 did not affect mouse fertility, but null mutation in IL-1 receptor reduced litter size (Ingman and Jones, 2008) suggesting that just IL1 is the main IL involved in control of ovarian functions. The IL-1 system components (IL-1alpha, IL-1beta, IL-1 receptor antagonist, IL-1 receptors) have been demonstrated to have several sites of synthesis in the ovary. These factors have been localized in the various ovarian cell types, such as the oocyte, granulosa and theca cells in several mammalian species. IL-1-like bioactivity has been reported in human and porcine follicular fluid at the time of ovulation. The role of IL-1 in local processes is still poorly known, although there is evidence for its ability to stimulate ovarian cell proliferation, suppress apoptosis, and therefore to promote ovarian follicular growth. On the other hand, IL1 was shown to inhibit formation of FSH and LH receptors, as well as both basal and gonadotropin-induced release of steroid hormones (Brannstrom, 2004). IL1 effect depends on stage of ovarian development: it inhibits steroidogenesis in undifferentiated follicles, but stimulates progesterone release in differentiated ovaries (Bornstein et al., 2004; Gérard et al., 2004). Furthermore, IL-1 may be involved in several ovulation-associated events such as the synthesis of proteases, regulation of plasminogen activator activity, prostaglandin and nitric oxide production. Finally, IL1 can affect (mailnly suppress) ovulation, affect release of progesterone and estradiol and promote production of prostaglandins E and F and their receptors in corpus luteum (Brannstrom, 2004; Bornstein et al., 2004; Gérard et al., 2004).

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There are indirect evidence for involvement of other interleukine, IL-8 in follicular development and atresia, ovulation, steroidogenesis, and corpus luteum function (Bornstein et al., 2004). In addition, ILs produced by immune and/or reproductive systems could be molecules mediating known suppressive effect of inflammation on reproductive processes. Some ovarian cancers are associated with increased IL1 production, which could be involved in altered steroidogenesis and increased proliferation of malignant ovarian cells (Bornstein et al., 2004). The ability of IL21 to prevent ovarian cancer has been recently reported (Dou et al., 2009). 3.4.19.4. Inhibin Inhibins (A and B) are other members of TGF-beta family. They can affect reproductive processes inhibiting pituitary FSH production (endocrine function) and controlling ovarian functions directly (paracrine and autocrine intraovarian regulation). Both inhibins and their receptors under stimulatory control of FSH and TGF beta are produced by ovarian granulosa, but probably not in theca cells. Inhibin B production is high in newly recruited, small antral follicles, whilst inhibin A is produced at maximal amounts by dominant follicle after preovulatory gonadotropin surge (Findlay et al., 2001; Chapman et al., 2004). Mice lacking inhibin were normal at birth, but females developed severe gonadal tumours (Ingman and Jones, 2008). At the level of pituitary, inhibins, together with GnRH and estrogens, inhibits FSH, but not LH release and, therefore, suppress all FSH-induced ovarian events (see above). At the level of the ovary, functions of inhibins are studies insufficiently and inconsistent. There are reports, that inhibin A can stimulate (Vitale et al., 2002) or inhibit apoptosis, stimulate estradiol release by granulosa cells (Denkova et al., 2004), as well as to augment LH-induced androgen release by theca cells (Chapman et al., 2004). It is proposed (Vitale et al., 2002), that inhibin, being produced by dominant follicle and inducing apoptosis in subordinate follicles could play an important role in follicular selection. Inhibin level could be useful index for prediction ovarian reserve and in vitro fertilisation outcome (Chapman et al., 2004; Broekmans et al., 2006). Furthermore, measurement of blood inhibin subunits could be useful for evaluation physiological and pathological state of the ovary. For example, mutation in genes encoding inhibin A, whose are associated with premature ovarian failure, could be one of cause of this ovarian disorder (Suzumori et al., 2007). Furthermore, inhibin A is a marker of dominant follicle and corpus

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luteum activity and decreases in polycystic ovary syndrome. Inhibin A increases in gestational diseases such as pre-eclampsia and fetal Down's syndrome, and this increase in inhibin A improves early diagnosis of both conditions. The measurement of inhibin A in women with threatened abortion provides useful information about the likelihood of pregnancy loss. Inhibin B increases markedly in women with granulosa cell tumor. On the contrary, inhibin B decreases in women with declining ovarian function and correlates with female response to ovulation induction (Tsigkou et al., 2008). 3.4.19.5. Activin/Follistatin System Activins (A, B and AB), member of TGF-beta family, act as locally produced paracrine factors in the ovary. They are physiological antagonists of inhibin, i.e. stimulators of FSH production, although its receptors and direct action on the ovary have been reported. After its release, activin binds a complex with the activin type II receptor ActRIIB, or with the binding proteins follistatin and follistatin-like 3 (Xia and Schneyer, 2009). The analysis of activin-related mutations demonstrated its importance in control of ovarian functions. Mutation in activin A and B or their receptors reduced or blocked female fertility, reduced ovarian growth and development, induced hypogonadism, defective folliculogenesis, reduced or absent fertility and suppressed FSH release. In some cases follicles developed, but not ovulated (Ingman and Jones, 2008) . Effects of administration of activin and its analogues demonstrated that activin could be promoter of ovarian granulosa cell proliferation, follicle development and selection, oocyte maturation and acquisition of developmental competence and luteolysis. Furthermore, through promotion of FSH release and of formation of FSH receptors, it can promote all FSH-dependent processes including responsibility of ovaries to gonadotropins. For example, it can increase the stimulatory effect of LH on androgen production by small and medium-sized antral follicles (Chapman et al., 2004; Knight and Glister, 2006; Xia and Schneyer, 2009) or promote preantral follicle growth and oocyte maturation (Thomas et al., 2003). Follistatin, which binds activin and reduces its bioavailability, exerts the effects oppose to activin. Female mices with overexpression of follictatin, have small ovaries and become infertile with advancing age. On the other side, the inactivation of granulosa cell specific follistatin gene resulted disrupting fertility through reducing numbers of ovarian follicles, fertilization defects and elevated gonadotropins, eventually leading to infertility. This phenotype is strikingly similar to symptoms of premature ovarian failure, supporting a role

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for tightly regulated activin bioactivity in maintaining normal ovarian function (Ingman and Jones, 2008). It is however to note, that the refered results of in-vivo experiments don‟t always enable to distinguish hypothalamo-hypophysial and intragonadal actions of activins and follistatins. In in-vitro experiments, activin and follistatin did not affect the number of primordial follicles entering the growing phase, but activin enhanced the subsequent follicular growth, not affecting apoptosis of follicular cells. Effects of activin were counteracted by follistatin (Silva et al., 2006). These in-vitro data suggested, that activin and follistatin are antagonists not only in their effects on FSH release from the pituitary, but also in their direct action on ovarian follicles. 3.4.19.6. Anti-Mullerian hormone (AMH) Anti-Mullerian hormone (AMH also known as Müllerian inhibitory substance) is a dimeric glycoprotein produced by ovarian granulosa cells. Although it can not been identified in humans until puberty (Visser et al., 2006), the most known biological effect of AMH is to inhibit primordial-toprimary follicle transition and further progression to antral stage in early ovarian follicullogenesis (Skinner, 2005; Knight and Glister, 2006). Moreover, it inhibits the action of FSH (Visser et al., 2006) and other known intraovarian stimulators of follicle transition, including basic fibroblast growth factor (bFGF), kit ligand (KITL), or keratinocyte growth factor (KGF). In primordial follicles is was found to alter the expression of 707 genes including inhibition of expression of factors stimulating primordial follicle development and TGF beta intracellular signaling pathway, as well as stimulation the expression of factors inhibiting this process (Nilsson et al., 2007). Although AMH is able to control apoptosis and steroidogenesis in non-ovarian cells, its action on these processes in the ovary seems have not been studied yet. Due to unique biological function of AMH, it could be potentially used for detection and prediction the ovarian reserve of follicles and illnesses associated with impaired initial and cyclic follicle recruitment and success of gonadotrpininduced ovarian cycle (Broekmans et al., 2006; Visser et al., 2006, Nelson et al., 2009).) 3.4.19.7. Bone Morphogenetic Proteins (BMPs) and Growth and Differentiation Factors (GDFs) BMPs and GDFs are signalling substances produced by oocyte, but affecting surrounding follicular cells. There is a body of evidence concerning the role of BMP-6, BMP-15 and GDF-9. These molecules, through their

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receptors in granulosa and cumular cells (Wang and Roy, 2009), are able to promote follicular cell proliferation, differentiation, glycolysis, cholesterol synthesis, follicle growth, sensitivity to FSH and LH and prevent luteinisation, progesterone and androgen production, apoptosis and follicular atresia (Knight and Glister, 2006; Mermillod et al., 2008). Mutations or deletion of genes encoding these growth factors induce disfunctional LH secretion, lack or desrupted follicullogenesis, impaired ovarian function and estrous cycles, reduced responsibility to FSH, reduced oocyte competence and number of ovulations, infertility and ovarian failure in mices, sheep and humans (Pangas, 2007, Ingman and Jones, 2008). BMP4 and BMP7, products of thecal ovarian cells, promotes recruitment and growth and suppress apoptosis and atresia of ovarian follicles at each stage of their development and suppress basal and LH-induced progesterone and androgen production. The inhibitory effect of BMP7 from thecal cells on follicular progesterone and androgen production is reported too (Knight and Glister, 2006; Pangas, 2007). BMP15 can affect the expression of inhibin and activin subunits in granulosa cells (Li et al., 2009). Since BMPs can be involved in control of follicular selection and number of ovulations, their practical use for prediction of fertility is possible (Hunter et al., 2004). In some cases mutations in GDF9 can be assiciated with premature ovarian failure (Simpson, 2008).

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Webb R, Campbell BK. Development of the dominant follicle: mechanisms of selection and maintenance of oocyte quality. Soc Reprod Fertil Suppl. 2007 64:141-163. Weems CW, Weems YS, Randel RD. Prostaglandins and reproduction in female farm animals. Vet J. 2006 171:206-228 Wunsch A, Sonntag B, Simoni M. Polymorphism of the FSH receptor and ovaria response to FSH. Ann Endocrinol (Paris). 2007 68:160-166. Xia Y, Schneyer AL. The biology of activin: recent advances in structure, regulation and function. J Endocrinol. 2009 202:1-12. Yao N, Lu CL, Zhao JJ, Xia HF, Sun DG, Shi XQ, Wang C, Li D, Cui Y, Ma X. A network of miRNAs expressed in the ovary are regulated by FSH. Front Biosci. 2009 14:3239-3245. Zachow R, Uzumcu M. The hepatocyte growth factor system as a regulator of female and male gonadal function. J Endocrinol. 2007 195:359-371. Zerani M, Boiti C, Zampini D, Brecchia G, Dall'Aglio C, Ceccarelli P, Gobbetti A. Ob receptor in rabbit ovary and leptin in vitro regulation of corpora lutea. J Endocrinol. 2004 183:279-288. Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJ. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science. 2005 310:996-999. Zieba DA, Amstalden M, Williams GL. Regulatory roles of leptin in reproduction and metabolism: a comparative review. Domest Anim Endocrinol. 2005 29:166-185. Ziecik AJ, Blitek A, Kaczmarek MM, Waclawik A, Bogacki M. Inhibition of luteolysis and embryo-uterine interactions during the peri-implantation period in pigs. Soc Reprod Fertil Suppl. 2006 62:147-61.

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Chapter 4

Protein Kinases in Control of Ovarian Functions

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Abstract Present review of available literature suggests, that ovarian cells produce a number of PKs, whose expression depends on type of cells, their state and action of hormones and other PKs. A number of PKs are involved in control of ovarian cell proliferation, apoptosis, oocyte maturation, hormone release, reception and response to hormones, as well as in mediating action of hormones on these ovarian functions. Complexity of interrelationships between different PK-dependent signaling pathways occurs. PKs and their regulators could be used for characterization, prediction and control of ovarian folliculogenesis and atresia, corpus luteum functions, oocyte maturation, fertility, release of hormones, response of ovarian structures to hormonal regulators, as well as for treatment of some reproductive disorders.

4.1. Introduction Protein kinases (PKs) is a large family of enzymes, whose key role in control of ovarian functions is well documented, and which could be practically used for regulation of reproductive processes. Despite the importance of PKs, the reviews concerning ovarian PKs published previously are focused on one PK (protein kinase A - Dupont, 2008, Aurora kinase -

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Macarulla et al., 2008) or particular group of PKs (Ca2+-dependent PKs – Ducibella and Fissore, 2008), one ovarian structure (oocyte – Brunet and Maro, 2005; Deckel et al., 2005, Kimura et al., 2008; corpus luteum - Diaz et al., 2002; Meidan et al., 2005; Gadsby et al., 2006), particular process (oogenesis - Brunet and Maro, 2005; Deckel et al., 2005, Kimura et al., 2008, cancerogenesis - Kamath and Buolamwini, 2006; Martin and Schilder, 2006; Markman, 2008) or hormone (FSH - Hillier, 2001; Richards et al., 2002; Hunzicker-Dunn and Maizels, 2006; Dupont et al., 2008). To our knowledge, no attempts to put together available data concerning involvement of different known PKs in control of different ovarian processes have been previously made. The present chapter tries to review available knowledge concerning involvement of different PKs in control of different ovarian functions (proliferation, apoptosis, hormone release, reception and response to hormones of ovarian follicular and luteal cells, oocyte maturation, fertility a.o.) in mammals and birds, possible interrelationships between different PKs and outline areas of their practical applications. Non-hormonal regulators of PKs, as well as details concerning mechanisms of action of PKs, which are well reviewed previously (Hunzicker-Dunn and Maizels, 2006; Ducibella and Fissore, 2008; Dupont et al., 2008 a.o.), are not discussed in details here.

4.2. Function and Classification of Protein Kinases PKs are enzymes catalyzing protein phosphorylation. Such phosphorylation results in a functional change of the substrate protein by changing its biological activity, cellular location, association and other interrelationships with other proteins. The human genome contains about 500 PK genes, which correspond to about 2% of all human genes (Manning, 2005). The Kinase KnowledgeBase (http://www.eidogen-sertanty.com/products_ kinasekb.html) lists totally 486 identified unique PKs, including 141 PKs with annotated assay data. The classification of PKs is based on their substrates and regulators. All PKs remove a phosphate group from ATP and covalently attach it to one of four amino acids that have a free hydroxyl - serine and threonine (superfamily of serine-treonine PKs), tyrosine (superfamily of tyrosine kinases, TK), serine, threonine and tyrosine (dual-specificity kinases) (Dhanasekaran et al., 1998) and histidine (histidine kinases) (Besant et al., 2003). Within these

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superfamilies there are sub-divisions of PKs based on their regulators. The most known representative of serine/threonine PKs are PKs regulated by cAMP (protein kinase A, PKA), cGMP (protein kinase G, PKG), some mitogens (mitogen-activated PKs, MAPK, aurora kinases, AK), cell cyclerelated proteins cyclins (cyclin-dependent PKs, CDKs), stress (Janus kinases, JNK), diacylglycerol (protein kinases C, PKCs), phosphatydil inositol (PI3 kinases, PI3K), Ca2+/calmodulin (calmodulin-dependent kinases, CaMKs) and rapamycin (target of rapamycin, TOR). The only currently known regulators of tyrosine kinases are growth factors. In some cases, such PK represents a part of growth factor receptor (Epidermal growth factor receptor – EGFR a.o.). An example of dual-specificity kinase could be a mitogen activated protein kinase kinase (MEK, MAPKK), which is involved in the MAP kinase cascade. Regulators of histidine kinases, which are expressed mainly in prokaryotic and fungal cells, are not well elucidated, although their presence in the islets beta cells and changes under influence of insulin have been reported (Kowluru, 2002). The PKs, after activation by extracellular regulators or their messengers listed above, phosphorylate specific target proteins, which are often enzymes (other PKs, transcription factors a.o.) themselves. Therefore, single PKs or their cascades play an important role in intracellular transduction of signals from extracellular factors to target genes involved in control of cell cycle, apoptosis, differentiation, and response to external stimuli. Some external factors (metabolism, growth factors, hormones) can exert their effect via different PKs and PK cascades. For example, melatonin action on non-ovarian cells is mediated through several cross-talking signalling cascades including PKA, MAPKs, PKCs, CaMKs and other PKs (Harderland, 2009). Classification, evolution and basic functions of PKs in non-ovarian cells are described in a special review (Manning, 2005).

4.3. Presence of Protein Kinases in the Ovary Although not all known PKs are demonstrated in the ovary, presence of members of MAPKs, CDKs, TKs (including EGFR), PI3K, Akt, PKA, AK, HER kinases, mTOR and activin receptor like kinase (ALK) families in ovarian follicular granulosa cells has been well documented (Shimada et al., 2001; Sirotkin et al., 2000, 2007; Makarevich et al., 2002, 2004b; Hunzicker-

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Dunn and Maizels, 2006; Kumar et al., 2007; Sawada et sl., 2007; Wang and Tsang, 2007; Dupont et al., 2008; Macarulla et al., 2008). Furthermore, observations of effects of activators and blockers of PKs indicate presence and importance of a number of other PKs in control of ovarian functions and in mediating effect of hormones on these functions (see below). For example, blockade of 88 PKs by siRNA constructs altered ovarian cell functions (Sirotkin et al., 2009, 2010). Presence of PKA and CDK/p34 in ovarian follicles is illustrated in Fig. 1. Occurrence of MAPKs (Meidan et al., 2005), PKCs (Gadsby et al., 2006) and PKA (Dupont et al., 2008) was demonstrated in ovarian corpus luteum. Representatives of PKA, MAPK, PI3K, Akt, CaMK, PKC, AK, Janus kinases (JNKs) and myosin light chain kinase (MLCK) are found in oocytes, whilst their expression and localization depends on stage of oocyte maturation (Sirotkin et al., 2000a,c; Kimura et al., 2007; Ducibella and Fissore, 2008; Lefèvre et al, 2007; Mermillod et al., 2008). Expression of PKs are influenced by some reproductive disorders indicating involvement of these PKs in control of these disorders (see below). For example, in ovarian tumors, substantial changes (mainly overexpression compared to healthy ovaries) in MAPKs, EGFR and other TKs, PK3K/Akt, HER kinases, mTOR a.o. are reported (Kamath and Buolamwini, 2006; Martin and Schilder, 2006; Kumar et al., 2007; Markman, 2008). Polycystic ovarian syndrome (PCOS) is associated with increased expression of MAPK/ERK1,2 and insulin receptor Ser kinase but reduced expression of PI3K and insulin receptor TK (Seow et al., 2007).

Chicken ovarian follicles contain protein kinase A and cdc2 kinase/p34

PKA

-47K

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Figure 1. Presence of PKA and CDK/p34 in cultured chicken ovarian follicles. SDS PAGEWestern blotting. (Sirotkin and Grossmann, not published data).

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Presence of PKs in the ovary is modulated by hormones. For example, FSH activates more than 100 genes in ovarian granulosa cells, some of which are encoding PKs, their regulators or targets (Hunzicker-Dunn and Maizels, 2006). Influence of FSH on ovarian PKA, MAPKs, CDKs, PI3K, Akt, CaMK, PKCs and other PKs (Gadsby et al., 2006; Hinzucker-Dunn and Maizels, 2006; Dupont et al., 2008; Lefèvre et al, 2008) has been documented. There are reports on the action of GH on ovarian PKA and MAPK/ERK1,2 (Sirotkin and Makarevich, 2002; Sirotkin et al., 2003; Sirotkin, 2005), leptin on PKA (Sirotkin et al., 2008), ghrelin on PKA, MAPK/ERK1,2 and CDK/p34 (Sirotkin and Grossmann, 2007,2008), oxytocin on PKA and MAPK/ERK1,2 (Makarevich et al., 2004), IGF-I, IGF-II and EGF on PKA, MAPK/ERK1,2, CDK/p34 (Makarevich et al., 2002, Sirotkin et al., 2002; Sirotkin and Grossmann, 2003, 2006), PI3K, p70S6K and mTOR (Hunzicker-Dunn and Maizels, 2006), thrombopoietin on PKA, TKs and CDK/p34 (Sirotkin et al., 2004). In corpus luteum TNF alpha alters expression of PKCs (Gadsby et al., 2006). In oocytes FSH can regulate PKA (Deckel, 2005) and meiosis activating sterol (FF-MAS) - MAPKs (Grøndahl, 2008). The ability of GH to promote accumulation of PKs in bovine ovarian granulosa cells is shown in Fig. 2. The influence of hormones on PKs is important in mediating effect of hormones on ovarian function through PK-dependent signalling pathways (see below).

4.4. Protein Kinases Control Ovarian Cell Proliferation Genome-wide screen of PKs, which blockade by siRNAs affected human granulosa cell proliferation showed, that 36% of PKs is involved in stimulation, but only 8% of PKs in inhibition of ovarian follicular cell cycle (Sirotkin et al., 2009, Fig. 3). Effect of pharmacological activators or blockers of PKs showed, that PKA, PKG, MAPKs, PI3K/Akt, CDKs, TKs and ALK can both promote (in some cases also suppress) ovarian granulosa cell proliferation (Makarevich et al., 2002, 2004; Tamura et al., 2004; Sirotkin and Grossmann, 2003, 2006; Wang and Tsang, 2007), although the ability of TKdependent intracellular signalling to stimulate ovarian folliculogenesis and ovulation is reported too (Matousek et al., 1999). The cAMP/PKA-dependent intracellular mechanisms can either inhibit (Peluso, 1993; Hsueh et al., 1996; Hillier and Tetsuka, 1997), stimulate (Cheadle et al., 2008; Viegas et al., 2008;

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Sirotkin et al., 2009; Chrenek et al., 2010) or not influence (Dupont et al., 2008) follicular cell proliferation, but other PKs are involved predominantly in promotion of ovarian cell cycle. 100

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Figure 2. GH promotes accumulation of PKA, MAPK/ERK1,2 and CDK/p34 in porcine ovarian granulose cells. Immunocytochemirstry. (Modified from Sirotkin and Makarevich, 1999, 2002).

The involvement of these and some other PKs in control of ovarian cell proliferation was confirmed by experiments with ovarian malignant cells. Pharmacological, siRNA- or antisense oligonucleotide-induced downregulation of PKCs (Fields and Regala, 2007; Suzuki and Hayashi, 2007), PI3K (Ma et al., 2006; Martin and Schilder, 2006; Lane et al., 2007; Noske et al., 2007), MAPK/MDM2 (Zeng et al., 2005; Martin and Schilder, 2006; Suga et al., 2007), TKs (Martin and Schilder, 2006; Kumar et al., 2007; Sawada et al., 2007) including EGFR (Kamath and Buolamwini, 2006 ), ALK7 (Xu et al., 2006), mTOR (Martin and Schilder, 2006), AK (Macarulla et al., 2008), and embryonic leucine zipper kinase (Melk) (Gray et al., 2005) can inhibit proliferation of ovarian carcinoma cells and reduce the growth of ovarian tumors. During corpus luteum development, PKs can be involved in stimulation of luteal cell proliferation. At this time, activation of genes related to several proliferation-related PK cascades occurs (Richards et al., 2002). One of such PK could be MAPKs. At least, prostaglandin F2 alpha can promote survival and proliferation of luteal cells and Corpus luteum vascularisation during its development via stimulation of phosphorylation of p42/44 MAPK (Meidan et al., 2005).

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Protein Kinases in Control of Ovarian Functions

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6 7 8 Figure 3. Effect of siRNAs blocking PKs on expression of proliferating cell nuclear 9 antigene (PCNA) in cultured human granulosa cells allows to identify PKs involved in control of human granulosa cells proliferation and siRNA constructs with potential anticancer action. Immunocytochemistry. (Sirotkin et al., 2009).

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4.5. Protein Kinases Control Ovarian Cell Apoptosis Genome-wide selected blockade of PKs by siRNAs showed, that 34% of PKs up-regulates, and less than 6% of PKs down-regulate human ovarian granulosa cell apoptosis (Sirotkin et al., 2009). The involvement of PKA, PKG, MAPKs, PI3K, CDKs, TKs and AK in control ovarian follicular cell apoptosis was shown by studies of effect of regulators of these PKs (Sirotkin et al., 2000a,b; Sirotkin and Makarevich, 2002; Makarevich et al., 2002, 2004; Wang and Tsang, 2007; Macarulla et al., 2008). MAPKs, CDKs, TKs, and PI3K/Akt, ALK and AK probably inhibit this process (Sirotkin and Makarevich, 1999, 2002; Makarevich et al., 2002, 2004; Wang and Tsang, 2007; Macarulla et al., 2008), and PKG stimulates it (Sirotkin et al., 2000a). cAMP/PKA can either up-regulate (Amsterdam et al., 2003; Spaczynski et al, 2005)-, dow-regulate (Vigas et al., 2008)- or not affect (Sirotkin and Makarevich, 1999, 2002; Sirotkin, 2005, Fig.4) ovarian cell apoptosis. On the other hand, genomic blockade of PKs in ovarian carcinoma cells revealed the pro-apoptotic action of PI3K/Akt system (Ma et al., 2006; Lane et al., 2007; Noske et al., 2007), MAPK/MDM2 (Zeng et al., 2005; Suga et al., 2007), TK/EphB4 (Kumar et al., 2007), TK/c-Met (Sawada et al., 2007), ALK7 (Xu et al., 2006) and Melk (Gray et al., 2005), but not of AK (Macarulla et al., 2008). Inhibition of mTOR promotes apoptosis in ovarian carcinoma cells (Martin and Schilder, 2006). In corpus luteum, activation of PKCs in mid-luteal phase can increase sensitivity of luteal cells to prostaglandin F2 alpha, which in turn initiate their apoptosis and subsequent corpus luteum resorption (Diaz et al., 2002; Gadsby et al., 2006).

4.6. Protein Kinases Control Maturation of Oocyte-Cumulus Complex Involvement of PI3K and CDKs in promotion of oocyte growth (McLaughin and McIver, 2009) and of PKA, PKG, MAPKs, PI3K, CDKs, TKs including EGFR, PKCs, CaMK and MLCK in control oocyte maturation and cytokinesis (Makarevich et al., 1997; Fan and Sun, 2004; Masciarelli et al., 2004; Brunet and Maro, 2005; Deckel, 2005; Motola et al., 2006; Lefèvre

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et al., 2007; Kimura et al., 2007; Ducibella and Fissore, 2008; Mermillod et al/. 2008) have been documented. Oocytes in the ovarian follicles are usually arrested at the first meiotic prophase, held in meiotic arrest by the surrounding follicle cells until a surge of gonadotropins from the pituitary or disconnection of oocyte from surrounding follicular cells stimulates the immature oocyte to resume meiosis. Cytoplasmic and, in lesser extent, nuclear maturation is promoted by FF-MAS produced by ovarian cells (Grøndahl, 2008). MAPKs, CDKs, PI3K, Akt (Shimada et al., 2001; Fan and Sun, 2004; Brunet and Maro, 2005; Lefèvre et al., 2007; Kimura et al., 2007), CaMK , MLCK (Brunet and Maro, 2005; Ducibella and Fissore, 2008) and EGFR (Motola et al. 2006) are promoters of meiosis resumption and progression, but other TKs (Makarevich et al., 1997) and PKCs (Lefèvre et al., 2007) seems to inhibit these processes. cAMP/PKA in rodents and, probably in humans can either promote (Dupont et al., 2008) or suppress (Masciarelli et al., 2004; Deckel, 2005) oocyte maturation, but in porcine and bovine oocytes it prevents (Dupont et al., 2008) or not influences (Sirotkin et al., 2000) meiosis reinitiation. Mechanisms of their action are known insufficiently and can vary in different species. Nevertheless, it is accepted, that meiosis is arrested by cytostatic factor (CSF) and promoted by maturation, meiosis or mitosis promoting factor (MPF), a complex of CDK/p34 and cyclin B1. MAPKs, PI3K/Akt, Janus kinases, AK and CaMK can affect production, action and stability of both MPF and CSF (Brunet and Maro, 2005). AK seems to be a major player in the phosphorylation cascade leading to MPF activation (Mermillod et al., 2008). AMP/PKA can prevent oocyte maturation via phosphorylation/inactivation of CDK1, a key component of MPF (Dupont et al., 2008). At further stages of oocyte maturation, an activation of MAPK is essential for the maintenance of metaphase II arrest, while its inactivation is a prerequisite for pronuclear formation after fertilization or parthenogenetic activation (Fan and Sun, 2004). In adition, Akt, JNK and AK, whose are activated during oocyte maturation, might not be related to MPF and meiosis, but to cytoplasmic oocyte maturation, i.e. accumulation and phosphorylation of proteins, mRNAs and other molecules and structures required for further fertilization and early embryo development (Mermillod et al., 2008).

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4.7. Protein Kinases Control Release of Hormones by Ovarian Cells As concerns ovarian follicular cells, the genome-wide search for PKs controlling steroid hormones release demonstrated, that 39% of PKs promotes and 14% of PKs inhibits progesterone release by human granulosa cells. 10% of PKs stimulates, and 19% of PKs inhibites the IGF-I output (Sirotkin et al., 2010). Effect of GH, Rp-cAMPS, genistein and their combinations on apoptosis in cultured bovine granulosa cells

*

% of apoptotic cells

80

* 60

40

*

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20

* *

0

Control

GH

PKA TK GH+PKA GH+TK blocker blocker blocker blocker

Figure 4. Blockers of protein kinase A (Rp-cAMPS) and tyrosine kinase (genistein) prevent the anti-apoptotic effect of GH on cultured bovine granulosa cells. TUNEL. (Sirotkin, 2005).

Studies of effect of pharmacological regulators of different PKs demonstrated involvement of PKA, PKG, MAPKs, PI3K/Akt, CDKs and TKs including EGFK in control of release of hormones by ovarian follicular cells (Makarevich et al., 1997, 2004; Sirotkin et al., 2000a, 2003; Hunziker-Dunn and Maizels, 2006; Motola et al., 2006; Sirotkin and Grossmann, 2003, 2006, 2007b; Hua et al., 2008; Dupont et al., 2008; Chrenek et al., 2010), as well as the importance of PKA and PKCs in control of hormones by corpus luteum (Diaz et al., 2002; Niswender, 2002) . Effect of pharmacological blockers or promoters of PKA on mammalian ovarian cells demonstrated, that PKA can promote release of oxytocin,

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IGFBP-3, PGF2 alpha (Sirotkin and Makarevich, 1999, 2002), IGF-I, progesterone and estradiol (Makarevich et al., 2004; Chrenek et al., 2010), although inhibitory action of PKA on ovarian progesterone, testosterone and estradiol release by mammalian ovarian follicular cells has been reported too (Dupont et al., 2008; Chrenek et al., 2010). In chicken, the ability of PKA either to promote or to suppress release of progesterone, testosterone, estradiol and arginine-vasotocin was reported (Sirotkin and Grossmann, 2006, 2007) Effects of stimulators and blockers of PKG showed, that PKG can be involved in stimulation of ovarian granulosa cell progesterone, and inhibition of IGF-I and oxytocin release (Sirotkin et al., 2000a,b) Action TK blockers demonstrated, that TKs can inhibit progesterone, estradiol, but not IGF-I and PGF-2 alpha output by mammalian granulosa cells and whole ovarian follicles (Makarevich et al., 1997), although other studies did not confirm the involvement of TK signalling pathways in control of synthesis of mammalian ovarian steroids, plasminogen activator or prostaglandins (Matousek et al., 1999). In chicken ovaries, TKs was shown to suppress release of estradiol and arginine-vasotocin, but not progesterone and testosterone (Sirotkin and Grossmann, 2003). The first studies did not reveal influence of MAPKs blockers on mammalian ovarian PGF2 alpha, PGE2 and OT secretion (Sirotkin et al., 2003), but subsequent experiments demonstrated, that MAPK can up-regulate PGF alpha and PGE2 output (Makarevich et al., 2004). In chicken ovarian cells, MAPKs are involved in promotion of arginine-vasotocin and in suppression of progesterone and estradiol release (Sirotkin and Grossmann, 2007a). CDKs (CDC2) inhibitor suppressed the secretion of arginine-vasotocin and stimulated or inhibited release of progesterone, but not of testosterone or estradiol by chicken ovarian cells (Sirotkin and Grossmann, 2006, 2007a). The role of CDKs in control of secretory activity of mammalian ovarian cells has not been studied yet. The involvement of EGFRK in promotion of progesterone release by mammalian ovarian cells has been reported (Motola et al., 2006). In corpus luteum PKA promotes progesterone release by large luteal cells. PKC, on the contrary, inhibits progesterone release and maintains luteal prostaglandin 2 alpha release (Diaz et al., 2002; Niswender, 2002).

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4.8. Protein Kinases Control Hormone Receptors and Response to Hormones Both stimulatory (LaPolt et al., 2003) and inhibitory (Peegel et al., 2005) action of cAMP/PKA, as well as an inhibitory effect of cGMP/PKG (LaPolt et al., 2003) on the expression of LH receptors in the ovary was reported. This suggests, that these PKs can modify action of hormones on ovarian cells. This hypothesis is supported by reports, that pharmacological stimulators of cAMP/PKA can increase the responsibility of ovarian cells to Gn-RH (Sirotkin et al.,1994; Ramakrishnappa et al., 2005; Sirotkin et al., 2009) and gonadotropins (Conti, 2002; Park et al., 2003; Masciarelli et al., 2004; McKenna et al., 2005; Hunzicker-Dunn and Maizels, 2006; Hua et al., 2008; 1 2Sirotkin et al., 2009a, 2010; Chrenek et al., 2010). Besides GnRH and 3gonadotropins, pharmacological regulators of cAMP/PKA can modify 4 5response of ovarian cells to GH (Sirotkin, 2005), IGF-I, IGF-II, EGF 6(Makarevich et al., 2000; Sirotkin et al., 2000; Chrenek et al., 2010), oxytocin 7 (Makarevich et al., 2004b), ghrelin (Chrenek et al., 2010), bone morphogenetic 8 9protein-4 (Pierre et al., 2004) and progestins (Peluso, 2006).

50

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10 11 a) b) 12 13 14 IGF-I Oxytocin 15 * GH alone 16 * * 17 18 * 19 * * GH alone 20 * * * * * * * * 21 GH+blocker GH+blocker * 22 23 0 1 10 100 1000 10000 0 1 10 100 1000 10000 24 GH dose added (ng/ml medium) GH dose added (ng/ml medium) 25 26 27 28 29Figure 5. PKA blocker inhibits stimulatory action of GH on the release of IGF-I (a) and 30oxytocin (b) by cultured bovine ovarian granulose cells RIA. (Sirotkin, 2005). 31 Blockers of PKA, CDKs (Sirotkin and Grossmann, 2006), TKs and 32 33MAPKs (Sirotkin and Grssmann, 2003) were able to prevent or reverse effects 34 35of IGF-II on chicken ovarian cells. Blockers of PKA, MAPKs and CDKs 36prevented or reversed action of ghrelin (Sirotkin and Grossmann, 2007) and 37 38 39 40 Figure 5: Nova PKAScience blocker inhibitsIncorporated, stimulatory action of GH on the release of IGF-I (a) and Regulators41 of Ovarian Functions, Publishers, 2014. ProQuest Ebook Central, 42 oxytocin (b) by cultured bovine ovarian granulose cells RIA. (Sirotkin, 2005) 25

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leptin (Sirotkin and Grossmann, 2008) on these cells. The ability of PKA and TKs to prevent the stimulatory effect of GH on apoptosis and on release of IGF-I and oxytocin is shown in Fig.4 and Fig.5. Therefore PKA, PKG, MAPKs and CDKs can increase responsibility of mammalian and avian ovarian cells to a number of hormonal regulators through an activation of hormone receptors.

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4.9. Protein Kinases Mediate Effect of Hormones on the Ovary The action of hormones on PKs and the ability of PKs regulators to promote, prevent or reverse action of hormones described above suggest, that hormones can control ovarian cell functions through up- or down-regulation of PKs. These two bodies of evidence demonstrated, that FSH can promote ovarian folliculogenesis, oocyte maturation and estrogen release via PKA, PI3 kinase, protein kinase B(Akt), CDKs, S10 histone H3 kinases, p38 MAPK, ERK1,2 MAPK, ribosomal S6 protein kinase (p70S6K), stress-activated protein kinases (MSK), p21-activated protein kinase, or aurora kinase B, glucocorticoid kinase (SGK), and the Ser/Thr kinase mammalian target of rapamycin (mTOR) a.o. (Richards et al., 2002; Hunzicker-Dunn and Maizels, 2006; Kimura et al., 2007; Ducibella and Fissore, 2008; Dupont et al., 2008; Lefèvre et al, 2008). LH promotes release of luteal progesterone and prostaglandin F2 alpha through PKA- and PKCs-dependent intracellular mechanisms (Diaz et al., 2002; Niswender et al., 2002). GnRH can promote oocyte maturation and progesterone release via EGFRK (Motola et al., 2006). GH (Sirotkin and Makarevich, 2002; Sirotkin, 2005) and oxytocin (Makarevich et al., 2004) can prevent apoptosis and stimulate release of ovarian hormones via PKA and MAPKs. Leptin (Sirotkin and Grossmann, 2007a,b; Sirotkin et al., 2007,2008) and ghrelin (Sirotkin and Grossmann, 2007, 2008; Chrenek et al., 2010) can regulate ovarian cell proliferation, apoptosis and secretory activity through PKA-, MAPK- and CDK-dependent intracellular mechanisms. IGF-I, IGF-II and EGF can promote ovarian cell proliferation and secretory activity through cAMP/PKA, cGMP/PKG, MAPK, PI3/Akt and glycogen synthase kinase (GSK) - dependent pathways (Makarevich et al., 2000; Richards et al., 2002; Makarevich et al., 2002; Sirotkin et al., 2002; Sirotkin and Grossmann, 2003, 2006; Dupont et al.,

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2008). The stimulatory effects of these growth factors on maturation of oocyte (Sirotkin et al., 2000; Deckel, 2005, Dupont et al., 2008; Kimura et al., 2008) are mediated through PKA, MAPKs, CDKs and EGFRK. Growth factors of TGF beta family promote ovarian cell apoptosis, ovarian follicle atresia and reduce proliferation in normal and malignant ovarian cells through ALKs (Wang and Tsang, 2007). TNF alpha induces corpus luteim regression through PKC (Gadsby et al., 2006). Progesterone prevents apoptosis, maintains survival and promotes proliferation of ovarian granulosa cells via the PKGdependent (Peluso, 2003) and CDK-dependent (Stouffer et al., 2007) pathways. FF-MAS promotes oocyte cytoplasmic maturation via MAPKdependent intracellular mechanisms (Grøndahl, 2008). Present figures suggest the interrelationships between GH and some PKs. The stimulatory effect of GH on accumulation of several PKs (Fig.2), as well as the ability of PK blockers to prevent the effect of GH on apoptosis (Fig.4) and release of IGF-I and oxytocin (Fig.5) suggest, that PKs can mediate action of GH on apoptosis and secretory activity of bovine ovarian granulosa cell. Some PKs mediating action of FSH on ovarian granulosa cell functions in different species are indicated in Fig. 6.

4.10. Interrelationships between Different Protein Kinases in the Ovary Hierarchical, cascade-like interactions, as well as cross-talk between different PKs occur within ovarian cells. For example, in ovarian granulosa cells, TKs can stimulate both PI3K (Sawada et al., 2007) and MAPK/ERK1,2, but inhibit CDK/p34 (Sirotkin and Grossmann, 2003) and PKA (Makarevich et al., 1997). PKG blockers promoted accumulation of cAMP and catalytic subunit of PKA, but inhibited accumulation of regulatory subunit of PKA (Sirotkin et al., 2000a). PKA, via histone H3 kinase, can activate both MAPKs and PI3K (Hunziker-Dunn and Maizels, 2006), whilst MAPKs, but not PI3K, can stimulate the downstream CDKs (Shimada et al., 2001). TKs suppress accumulation of MAPK/ERK1,2 and promote accumulation of CDK/p34. On the contrary, MAPKs stimulates expression of CDK/p34 suggesting existence of TK-MAPK-CDK axis (Sirotkin and Grossmann, 2003).

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Figure 6. Interrelationships between some PK-dependent intracellular signaling pathways (dependent on PKA, PI3K, Akt, mTOR, histone H3K, EGFR, MAPK) in ovarian granulosa cells (Hunzicker-Dunn and Maizels, 2006).

A number of ovarian functions (if not all) is regulated not by one PK, but by a cascade of PKs. For example, PKA can inhibit progesterone release by follicular cells in different mammalian species through inhibition of MAPKs (Dupont et al., 2008). ALK7 promotes ovarian cell apoptosis through phosphorylation/activation of PI3K, which in turn inactivates anti-apoptotic Akt (Wang and Tsang, 2007). Some hierarchical interrelationships between different PKs mediating action of FSH on ovarian granulosa cells are present in Fig. 6. From theoretical viewpoints, these data suggest the complex interrelationships between different PKs-dependent intracellular signaling pathways. From practical viewpoints, they demonstrate, that each reproductive process could be controlled by several regulators targeting different PKs.

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4.11. Protein Kinases can be used for Control of Fertility, Ovarian Cycle and Health Despite a number of evidence for involvement of a variety of PKs in control of different ovarian functions, only few attempts were previously made to use it in practice for control of animal or human fertility, whilst reported attempts concerned exclusively PKA. Pharmacological blockers of cAMP-specific phosphodiesterases can control sexual maturation and ovarian cyclicity (Wang et al., 2007). Mice, deficient in cAMP-specific phosphodiesterases – activators of PKA, have impaired differentiation of ovarian cells, their response to gonadotropin, oocyte maturation, ovulation and fertility (Conti, 2002; Masciarelli et al., 2004). On the other hand, administration of PKA activators increased the number of ovulations, embryos and born pups in rats (McKenna et al., 2005), number of ovulation, ovulated oocytes, developed embryos, pregnancy rate, birth rate, litter size and litter weight in rabbits (Sirotkin et al., 2008a; 2009), as well as the number of fertilized oocytes in womens suffered from PCOS (Dupont et al., 2008). In addition, inhibitors of PKA, but not of TKs or PKCs suppressed, whilst activator of PKA promoted transport of ovulated egg via rat oviduct (Orihuella et al., 2003). Therefore, regulators of PKA could be potentially useful for improvement of reproductive processes in both ovary and oviduct. Despite lack of information concerning practical application of other PKs for control of reproductive processes, the available data of basic studies enable to outline possible areas of application of PKs in assisted reproduction, biotechnology, human and veterinary medicine. Regulators of PKA, PKG, MAPKs, PI3K, Akt, CDKs, TKs and ALK affecting ovarian follicular cell proliferation (Peluso, 1993; Hsueh et al., 1996; Hillier and Tetsuka, 1997; Matousek et al., 1999; Makarevich et al., 2002, 2004; Tamura et al., 2004; Sirotkin and Grossmann, 2003, 2006; Wang and Tsang, 2007; Dupont et al., 2008; Cheadle et al., 2008; Viegas et al., 2008) can be used for stimulation of ovarian folliculogenesis, increase in number of ovulations and, perhaps, for control of hypogonadism, PCOS and other ovarian disorders associated with impaired follicular growth. Molecules targeting PKs controlling corpus luteum cell proliferation (MAPK, Richards et al., 2002; Meidan et al., 2005), apoptosis and response to hormonal inductors of luteolysis (PKC, Diaz et al., 2002; Gadsby et al., 2006)

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could be potentially useful for control of luteal phase of ovarian/menstrual cycle, fertility, synchronisation of cycles in animal and human assisted reproduction, as well as for treatment of persistent corpus luteum or other other disorders of the ovarian cycle. Regulators of PKA, PKG, MAPKs and CDKs, which can increase formation of receptors to hormonal stimulators and responsibitily of ovarian cells to these stimulators (Sirotkin et al.,1994; Conti, 2002; Park et al., 2003; LaPolt et al., 2003; Peegel et al., 2005; Ramakrishnappa et al., 2005; Masciarelli et al., 2004; McKenna et al., 2005; Hunzicker-Dunn and Maizels, 2006; Hua et al., 2008) can be useful for improvement of hormone-mediated induction of ovulation and superovulation in assisted reproduction, treatment of infertility or, on the contrary, for improvement of hormonal contraception. For example, stimulatory effect of gonadotropins on rodent reproduction could be increased by addition of phosphodiesterase iunhibitors activating PKA (McKenna et al., 2005; Sirotkin et al., 2008, 2009). Beneficial effect of FFMAS on fecundity of womens suffered from PCOS (Grøndahl, 2008) could be principally improved by stimulating its mediator MAPK. Alteration in PKA, PKG, MAPKs, PI3K, CDKs, TKs including EGFRK, PKCs and CaMK within the oocytes which could affect their growth (McLaughin and McIver, 2009) and maturation (Makarevich et al., 1997; Sirotkiin, 2000; Fan and Sun, 2004; Masciarelli et al., 2004; Brunet and Maro, 2005; Deckel, 2005; Motola et al., 2006; Lefèvre et al., 2007; Kimura et al., 2007; Dupont et al., 2008; Ducibella and Fissore, 2008) could be applicable in animal and human in-vitro maturation and fertilization programmes for induction of oocyte nuclear maturation, synchronization of nuclear and cytoplasmic maturation or, on the contrary, as potential contraceptive agents. In addition, expression of these PKs within the oocyte could be marker for their selection for in-vitro maturation and fertilization. PKA, PKG, MAPKs, PI3K/Akt, CDKs, TKs and EGFK, which are regulators as well as mediators of ovarian follicular (Makarevich et al., 1997, 2004; Sirotkin et al., 2000a, 2003; Hunziker-Dunn and Maizels, 2006; Motola et al., 2006; Sirotkin and Grossmann, 2003, 2006, 2007b; Dupont et al., 2008; Sirotkin et al., 2009; Chrenek et al., 2010) and luteal (Diaz et al., 2002; Niswender, 2002) hormones, could be used for regulation of all hormonedependent reproductive events and for prevention of hormone-dependent disorders including hormone-related cancer. Malignant transformation of ovarian cells is one of frequently appeared and dangerous reproductive disorder. It is frequently associated with mutation and/or overexpression of some PKs (Fig. 7). It was mentioned previously, that

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suppression of PKC (Fields and Regala, 2007; Suzuki and Hayashi, 2007), PI3K (Ma et al., 2006; Martin and Schilder, 2006; Lane et al., 2007; Noske et al., 2007), MAPK/MDM2 (Zeng et al., 2005; Ma et al., 2006; Martin and Schilder, 2006; Suga et al., 2007), TKs (Martin and Schilder, 2006; Kumar et al., 2007; Sawada et al., 2007) including EGFR (Kamath and Buolamwini, 2006 ), ALK7 (Xu et al., 2006), TOR (Martin and Schilder, 2006), AK (Macarulla et al., 2008), and Melk (Gray et al., 2005) can reduce viability and proliferation of ovarian carcinoma cells, their response to hormonal stimulators of their malignancy (steroid hormones and growth factors), resulted in growth of ovarian tumors, as well as in increase of their responsibility to anti-cancer treatments. The hierarchical interrelationships between some PKs involved in human tumorgenesis are present in Fig.8. These PKs and their regulators could be used for prediction, prevention and treatment of ovarian cancer.

Figure 7. Interrrelationships between some PK-dependent pathways (PKC, EGFR, PI3K, MAPK, PKA) in control of human tumorgenesis. Phosphorylation s indicated as “P”. Components mutated in human tumors are indicated by yellow (Fields and Regala, 2007).

Therefore, PKs and their regulators could be potentially used for characterization, prediction and control of ovarian folliculogenesis and atresia, corpus luteum functions, oocyte maturation, fertility, release of hormones, response of ovarian structures to hormonal regulators, as well as for treatment

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of some reproductive disorders in assisted reproduction, biotechnology, human and veterinary medicine.

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Kimura N, Hoshino Y, Totsukawa K, Sato E. Cellular and molecular events during oocyte maturation in mammals: molecules of cumulus-oocyte complex matrix and signalling pathways regulating meiotic progression. Soc Reprod Fertil Suppl. 2007 63:327-42. Knight PG, Glister C. TGF-beta superfamily members and ovarian follicle development. Reproduction. 2006 132:191-206. Kowluru A. Identification and characterization of a novel protein histidine kinase in the islet beta cell: evidence for its regulation by mastoparan, an activator of G-proteins and insulin secretion". Biochem. Pharmacol. 2002 63: 2091–2100. Kumar SR, Masood R, Spannuth WA, Singh J, Scehnet J, Kleiber G, Jennings N, Deavers M, Krasnoperov V, Dubeau L, Weaver FA, Sood AK, Gill PS. The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome. Br J Cancer. 2007 96:1083-1091. Lane D, Robert V, Grondin R, Rancourt C, Piché A. Malignant ascites protect against TRAIL-induced apoptosis by activating tle PI3K/Akt pathway in human ovarian carcinoma cells. Int J Cancer. 2007 121:1227-1237. LaPolt PS, Leung K, Ishimaru R, Tafoya MA, You-hsin Chen J. Roles of cyclic GMP in modulating ovarian functions. Reprod Biomed Online. 2003 6:15-23. Lefèvre B, Pesty A, Courtot AM, Martins CV, Broca O, Denys A, Arnault E, Poirot C, Avazeri N. The phosphoinositide-phospholipase C (PI-PLC) pathway in the mouse oocyte. Crit Rev Eukaryot Gene Expr. 2007 17:259269. Ma Y, Yu WD, Kong RX, Trump DL, Johnson CS. Role of nongenomic activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated dinase kinase/extracellular signal-regulated kinase 1/2 pathways in 1,25D3-mediated apoptosis in squamous cell carcinoma cells. Cancer Res. 2006 66:8131-8138. Macarulla T, Ramos FJ, Tabernero J. Aurora kinase family: a new target for anticancer drug. Recent Patents Anticancer Drug Discov. 2008 3:114-122. Makarevich A, Sirotkin A, Taradajnik T, Chrenek P. Effects of genistein and lavendustin on reproductive processes in domestic animals in vitro. J Steroid Biochem Mol Biol. 1997 63:329-37. Makarevich A, Sirotkin A, Chrenek P, Bulla J, Hetenyi L. The role of IGF-I, cAMP/protein kinase A and MAP-kinase in the control of steroid secretion, cyclic nucleotide production, granulosa cell proliferation and preimplantation embryo development in rabbits. J Steroid Biochem Mol Biol. 2000 73:123-133. Makarevich AV, Sirotkin AV, Chrenek P, Bulla J. Effect of epidermal growth factor (EGF) on steroid and cyclic nukleotide secretion, proliferation and

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ERK-related MAP-kinase in cultured rabbit granulosa cells. Exp Clin Endocrinol Diabetes. 2002 110:124-129. Makarevich AV, Sirotkin AV, Genieser HG. Action of protein kinase A regulators on secretory activity of porcine granulosa cells in vitro. Anim Reprod Sci. 2004a 81:125-136. Makarevich AV, Sirotkin AV, Franek J, Kwon HB, Bulla J. The role of oxytocin, protein kinase A, and ERK-related MAP-kinase in the control of porcine ovarian follicle functions. Exp Clin Endocrinol Diabetes. 2004b 112:108-114. Manning G. Genomic overview of protein kinases. WormBook. 2005 13:1-19. Markman M. The promise and perils of 'targeted therapy' of advanced ovarian cancer. Oncology. 2008 74:1-6. Martin L, Schilder RJ. Novel non-cytotoxic therapy in ovarian cancer: current status and future prospects. J Natl Compr Canc Netw. 2006 4:955-66. Masciarelli S, Horner K, Liu C, Park SH, Hinckley M, Hockman S, Nedachi T, Jin C, Conti M, Manganiello V. Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of fiale infertility. J Clin Invest. 2004 114:196-205. Matousek M, Mikuni M, Mitsube K, Yoshida M, Brännström M. Inhibition of ovulation by tyrosine kinase inhibitors in the in vitro perfused rat ovary. J Reprod Fertil. 1999 117:379-385. McKenna S.D., Pietropaolo M., Tos E.G., Clark A., Fischer D, Kagan D., Bao, B., Chedrese P.J., Palmer S. Pharmacological inhibition of phosphordiesterase 4 triggers ovulation in follicle-stimulating hormone-primed rats. Endocrinology, 2005 146: 208-214. McLaughlin EA, McIver SC. Awakening the oocyte: controlling primordial follicle development. Reproduction. 2009 137:1-11. Meidan R, Levy N, Kisliouk T, Podlovny L, Rusiansky M, Klipper E. The yin and yang of corpus luteum-derived endothelial cells: balancing life and death. Domest Anim Endocrinol. 2005 29:318-328. Mermillod P, Dalbiès-Tran R, Uzbekova S, Thélie A, Traverso JM, Perreau C, Papillier P, Monget P. Factors affecting oocyte quality: who is driving the follicle? Reprod Domest Anim. 2008 43 Suppl 2:393-400. Motola S, Cao X, Ashkenazi H, Popliker M, Tsafriri A. GnRH actions on rat preovulatory follicles are mediated by paracrine EGF-like factors. Mol Reprod Dev. 2006 73:1271-1276. Niswender GD. Molecular control of luteal secretion of progesterone. Reproduction. 2002 123:333-339. Noske A, Kaszubiak A, Weichert W, Sers C, Niesporek S, Koch I, Schaefer B, Sehouli J, Dietel M, Lage H, Denkert C. Specific inhibition of AKT2 by RNA interference results in reduction of ovaria cancer cell proliferation: increased expression of AKT in advanced ovarian cancer. Cancer Lett. 2007 246:190-200.

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Orihuela PA, Parada-Bustamante A, Cortés PP, Gatica C, Croxatto HB. Estrogen receptor, cyclic adenosine monophosphate, and protein kinase A are involved in the nongenomic pathway by which estradiol accelerates oviductal oocyte transport in cyclic rats. Biol Reprod. 2003 68:1225-1231. Park CM, Kim SH, Kim SH, Moon MH, Kim KW, Choi HJ. Recurrent ovarian malignancy: patterns and spectrum of imaging findings. Abdom Imaging. 2003 28:404-415. Peegel H, Towns R, Nair A, Menon KM. A novel mechanism for the modulation of luteinizing hormone receptor mRNA expression in the rat ovary. Mol Cell Endocrinol. 2005 233:65-72. Peluso JJ. Multiplicity of progesterone's actions and receptors in the mammalian ovary. Biol Reprod. 2006 75:2-8. Pierre A, Pisselet C, Dupont J, Mandon-Pépin B, Monniaux D, Monget P, Fabre S. Molecular basis of bone morphogenetic protein-4 inhibitory action on progesterone secretion by ovine granulosa cells. J Mol Endocrinol. 2004 33:805-817. Ramakrishnappa N, Rajamahendran R, Lin YM, Leung PC. GnRH in nonhypothalamic reproductive tissues. Anim Reprod Sci. 2005 88:95-113. Richards JS, Russell DL, Ochsner S, Hsieh M, Doyle KH, Falender AE, Lo YK, Sharma SC. Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization. Recent Prog Horm Res. 2002 57:195-220. Sawada K, Radjabi AR, Shinomiya N, Kistner E, Kenny H, Becker AR,Turkyilmaz MA,Salgia R, Yamada SD, Vande Woude GF, Tretiakova MS, Lengyel E. c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res. 2007 67:1670-1679. Seow KM, Juan CC, Hsu YP, Hwang JL, Huang LW, Ho LT. Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery. Hum Reprod. 2007 22:1003-1010. Shimada M, Zeng WX, Terada T. Inhibition of phosphatidylinositol 3-kinase or mitogen-activated protein dinase kinase leads to suppression of p34(cdc2) kinase activity and meiotic progression beyond the meiosis I stage in porcine oocytes surrounded with cumulus cells. Biol Reprod. 2001 65:442-448. Sirotkin AV. Control of reproductive processes by growth hormone: extra- and intracellular mechanisms. Vet J. 2005 170:307-317. Sirotkin AV, Grossmann R.Role of tyrosine kinase- and MAP kinasedependent intracellular mechanisms in control of ovarian functions in the domestic fowl (Gallus domesticus) and in mediating effects of IGF-II. J Reprod Dev. 2003 49:99-106.

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Sirotki AV, Grossmann R. The role of protein kinase A and cyclin-dependent (CDC2) kinase in the control of basal and IGF-II-induced proliferation and secretory activity of chicken ovarian cells. Animal Reprod. Sci. 2006 92:169-181. Sirotkin AV, Grossmann R. The involvement of leptin, MAP kinase- and CDC2 kinase-dependent intracellular mechanisms in the control of hormone release by chicken ovarian granulosa cells. Slovak J. Animal Sci. 41:6-11 (2007a) Sirotkin AV, Grossmann R. The role of ghrelin and some intracellular mechanisms in controlling tle secretory activity of chicken ovarian cells. Comp Biochem Physiol A Mol Integr Physiol. 2007b 147:239-246. Sirotkin AV, Makarevich AV. GH regulates secretory activity and apoptosis in cultured bovine granulosa cells through the activation of the cAMP/protein kinase A system. J Endocrinol. 1999 163:317-327. Sirotkin AV, Makarevich AV Growth hormone can regulate functions of porcine ovarian granulosa cells through the cAMP/protein kinase A system. Anim Reprod Sci. 2002 70:111-126. Sirotkin AV, Makarevich AV, Pivko J, Kotwica J, Genieser H, Bulla J. Effect of cGMP analogues and protein kinase G blocker on secretory activity, apoptosis and the cAMP/protein kinase A system in porcine ovarian granulosa cells in vitro. J Steroid Biochem Mol Biol. 2000a 74:1-9. Sirotkin AV, Makarevich AV, Genieser HG, Kotwica J, Hetényi L. Effect of four cGMP analogues with different mechanisms of action on hormone release by porcine ovarian granulosa cells in vitro. Exp Clin Endocrinol Diabetes. 2000b 108:214-219. Sirotkin AV, Dukesová J, Makarevich AV, Kubek A, Bulla J. Evidence that growth factors IGF-I, IGF-II and EGF can stimulate nuclear maturation of porcine oocytes via intracellular protein kinase A. Reprod Nutr Dev. 2000c 40:559-569. Sirotkin AV, Chrenek P., Curlej J., Zahradnikova M. Effect of 3-isobutylmethyl-xanthine on rabbit superovulation and egg recovery. Slovak J. Animal Sci. 2008a 41:57-59. Sirotkin AV, Mlynček M, Makarevich AV, Florkovičová I, Hetényi L. Leptin affects proliferation-, apoptosis- and protein kinase A-related peptides in human ovarian granulosa cells. Physiol Res. 2008b 57:437-442. Sirotkin AV, Ovcharenko D, Benco A, Mlyncek M. Protein kinases controlling PCNA and p53 expression in human ovarian cells. Funct Integr Genomics. 2009a 9:185-195. Sirotkin AV, Chadio S, Chrenek P, Xylouri E, Fotopouloy H. Phosphodiesterase inhibitor 3-isobutyl-methyl-xanthine affects reproductive function in rabbit females. I. Stimulation of reproduction. Theriogenology. 2009b [Epub ahead of print, PubMed PMID: 19879640].

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Sirotkin AV, Ovcharenko D, Mlyncek M. Identification of protein kinases that control ovarian hormone release by selective siRNAs. Mol. Cell Endocrinol. 2010 44:45-53. Skinner MK. Regulation of primordial follicle assembly and development. Human Reproduction Update 2005 11:461–471. Spaczynski RZ, Tilly JL, Mansour A, Duleba AJ. Insulin and insulin-like growth factors inhibit and luteinizing hormone augments ovarian thecainterstitial cell apoptosis. Mol Hum Reprod. 2005 11:319-324. Stouffer RL, Xu F, Duffy DM. Molecular control of ovulation and luteinization in the primate follicle. Front Biosci. 2007 12:297-307. Suga S, Kato K, Ohgami T, Yamayoshi A, Adachi S, Asanoma K, Yamaguchi S, Arima T, Kinoshita K, Wake N. An inhibitory effect on cell proliferation by blockage of the MAPK/estrogen receptor/MDM2 signal pathway in gynecologic cancer. Gynecol Oncol. 2007 105:341-350. Suzuki K, Hayashi T. Protein C and its inhibitor in malignancy. Semin Thromb Hemost. 2007 33:667-72. Tamura M, Nakagawa Y, Shimizu H, Yamada N, Miyano T, Miyazaki H. Cellular functions of mitogen-activated protein kinases and protein tyroxine phosphatases in ovarian granulosa cells. J Reprod Dev. 2004 50:47-55. Viegas LR, Hoijman E, Beato M, Pecci A. Mechanisms involved in tissuespecific apopotosis regulated by glucocorticoids. J Steroid Biochem Mol Biol. 2008 109:273-278. Wang H, Tsang BK. Nodal signalling and apoptosis. Reproduction. 2007 133:847-853. Wang Z, Shi F, Jiang YQ, Lu LZ, Wang H, Watanabe G, Taya K. Changes of cyclic AMP levels and phosphodiesterase activities in the rat ovary. J Reprod Dev. 2007 53:717-725. Xu G, Zhou H, Wang Q, Auersperg N, Peng C. Activin receptor-like kinase 7 induces apoptosis through up-regulation of Bax and down-regulation of Xiap in normal and malignant ovarian epithelial cell lines. Mol Cancer Res. 2006 4:235-246. Zeng P, Wagoner HA, Pescovitz OH, Steinmetz R. RNA interference (RNAi) for extracellular signal-regulated kinase 1 (ERK1) alone is sufficient to suppress cell viability in ovarian cancer cells. Cancer Biol Ther. 2005 4:961-967.

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Chapter 5

Transcription Factors in Control of Ovarian Functions

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Abstract This chapter represents a review of contemporarily knowledge concerning involvement of transcription factors in control of different ovarian functions. After introduction of basic functions and classification of transcription factors, the available data concerning involvement of transcription factors in control of the following ovarian events are present: follicular development and selection, ovarian cell proliferation and cancerogenesis, ovarian cell apoptosis, ovarian secretory activity, oocyte/cumulus maturation, ovulation and luteogenesis, mediation effect of hormones, growth factors and cytokines. The importance of transcription factors of Smad family, of forkhead transcription factor (Fox) family, of breast cancer associated genes/transcription factor, hypoxia-induced transcription factors (HIFs) and of other transcription factors in control of these processes has been demonstrated.

5.1. Function and Classification of Transcription Factors Transcription factors are proteins that control gene expression by binding to specific DNA and thereby controls gene transcription (transfer of genetic information from DNA to mRNA) via up- and down-regulation of RNA (the

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enzyme that performs the transcription of genetic information from DNA to RNA) or other regulatory proteins. Transcription factors contain one or more DNA-binding domains, which attach to specific sequences of DNA adjacent to the genes that they regulate. After binding to DNA, the second, activator domain of transcription factors can stabilize or block the binding of RNA polymerase to DNA, catalyze the acylation or deacylation of histone proteins or recruit coactivator or corepressor proteins to the transcription factor DNA komplex (Narlikar et al., 2002). In humans the existence of more than 2000 transcription factors is proposed (Brivanlou and Darnell, 2002) and more than 700 proteomes are published (Wilson et al., 2008). The most populár classification of transcription factors is based on thein sequence similarity and hence the tertiary structure of their DNA-binding domains (Stegmaier et al., 2004; http://www.nlm.nih.gov/cgi/mesh/2009 /MB_cgi?mode=&term=Transcription+Factors). According to this classification, transcription factors could be dividend into several superclasses: 1. Superclass: Basic Domains (Basic-helix-loop-helix) including CREB (cAMP response element binding), 2. Superclass: Zinc-coordinating DNA-binding domains including steroid hormone receptors, GATA-Factors (binds sequence GATA), 3. Superclass: Helix-turn-helix (including fork head transcription factors, heat shock factors, HSF and transcriptional enhancer factor, TEAs), 4. Superclass: beta-Scaffold Factors with Minor Groove Contacts including NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells), STAT Signal Transducers and Activator of Transcription), p53 (tumor protein 53) and TATA (5'-TATAAA-3') binding proteins. 5. Superclass: Other Transcription Factors. Activity of transcription factors is regulated by their ligands, phosphorylation by protein kinases and other transcription factors and coregulatory proteins. Only small proportion of known transcription factors have been demonstrated to be involved in control of ovarian cells functions. In contrast to hormones and protein kinases, the pharmacological regulators are developed and used for study and control of only steroid hormones receptors, but not for the majority of known transcription factors, whilst genomic regulation has been used only recently. Substantial number of knowledge concerning involvement of transcription factors in control of ovary are based more on

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indirect evidences (observation of association between expression of these factors and particular ovarian events) than on direct evidences (experimental studies of effect of transcription factor up- and down-regulation). Association of particular transcription factor with particular physiological and pathological ovarian event does not always enables to descover properly biological functions of this molecule. The following review represents some examples of involvement of particular transcription factors in control of ovarian follicullogenesis, selection, ovarian cell proliferation and cancerogenesis, apoptosis, secretory activity, oocyte maturation and response to other hormones. The role of receptors to steroid hormones, which represents a topic of some special reviews (Peluso, 2007; Lafky et al., 2008; Li et al., 2008b; Walters et al., 2008), is not described in details here.

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5.2.1. Transcription Factors of Smad Family The involvement of different transcription factors of Smad family in control of of ovarian follicullogenesis and resulted fertility was demonstrated by a number of studies. Knock-out of Smad1 and Smad5 genes in mices induced impaired primordial germ cell development. Smad3 deficient mice exhibit impaired folliculogenesis and reduced fertility (Kaivo-oja et al., 2006). In subsequent studies, granulosa cell ablation of individual Smad2 or Smad3 caused insignificant changes in female fertility, deletion of both Smad2 and Smad3 led to dramatically reduced female fertility and fecundity. These defects were associated with the disruption of multiple ovarian processes, including follicular development, ovulation, and cumulus cell expansion (Li et al., 2008a). Smad4 ovarian-specific knockout mice are subfertile with decreasing fertility over time and multiple defects in folliculogenesis including premature luteinisation of ovarian granulosa cells, whose can induce symptoms resembling human premature ovarian failure (Pangas et al., 2006).

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5.2.2. Transcription Factors of Forkhead Transcription Factor (Fox) Family Forkhead L2 (FOXL2) is a member of the forkhead/hepatocyte nuclear factor 3 gene family of transcription factors and acts as a transcriptional repressor of the Steroidogenic Acute Regulatory (StAR) gene, a marker of granulosa cell differentiation. FOXL2 may play a role in ovarian follicle maturation and prevent premature follicle depletion leading to premature ovarian failure (Kuo et al., 2009). The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian failure (Moumné et al., 2008; Beysen et al., 2009). Fox12 is considered as one of key somatic sex determination and ovarian development (Ottolenghi et al., 2007). Mutations in Foxl2 can impair granulosa cell function, formation and development of ovarian follicles and induce infertility in mices, but not in humans. Fox12 can be involved in development of goat polled intersex syndrome, in which FoxL2 expression is severely reduced (Uhlenhaut and Treier, 2006). Nuclear FOXO3 can be responsible for the reversible maintenance of follicles in a quiescent state (Ottolenghi et al., 2007).

5.2.3. Other Transcription Factors Analysis of transgenic mices deficient to particular transcription factors demonstrated, that some transcription factor-related genes expressed in the germ cells such as Figla, Nobox, Kit and Ntrk2, as well as genes expressed in the surrounding somatic cells such as Foxl2, Kitl and Ngf, play critical roles during early folliculogenesis (Choi and Rajkovic, 2006). Comparison of small and large fillicles demonstrated the association of follicle growth and the expression of transcription factors TATA binding protein, E2F and CAAT binding protein (Sharma et al., 2009) and Ptch1 (Spicer et al., 2009) indicating that these transcription factors could be involved in control of ovarian follicullogenesis. Comparison of dominant and subordinate follicles demonstrated, that follicular dominance is associated with decrease in granulosa cell expression of mRNA for several newly described transcription

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factors - CEBP-beta (responsible for luteinization), SRF (regulates cell survival), FKHRL1 (stimulates apoptosis), NCOR1 (modulation of the actions of the estradiol receptor) and Midnolin (control of development via regulation of mRNA transport in cells) (Zielak et al., 2008).

5.3. Transcription Factors Involved in Control of Ovarian Cell Proliferation And Cancerogenesis

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5.3.1. Breast Cancer Associated Genes/Transcription Factor Breast cancer associated gene 1 (BRCA1) predisposes women to ovarian cancers. Mounting evidence indicates that BRCA1 is involved in all phases of the cell cycle and regulates orderly events during cell cycle progression. BRCA1 deficiency, consequently causes abnormalities in the S-phase checkpoint, the G(2)/M checkpoint, the spindle checkpoint and centrosome duplication. On the other hand, BRCA1 deficiency triggers cellular responses to DNA damage that blocks cell proliferation and induces apoptosis. Thus BRCA1 mutant cells cannot develop further into full-grown tumors (Deng, 2006; Kim and Chen, 2008). Germline mutations in BRCA1 and BRCA2 are responsible for a large proportion of hereditary breast and ovarian cancers. Soon after the identification of both genes the mouse models for the associated disease were developed. Application of these models provided evidence, that BRCA2 as an integral component of the homologous recombination machinery, whereas BRCA1 is an E3 ubiquitin ligase that has an impact on DNA repair, transcriptional regulation, cell-cycle progression and meiotic sex chromosome inactivation (Boulton, 2006).

5.3.2. Transcription Factors of Forkhead Transcription Factor (Fox) Family Expression levels of FOXL2 in a series of juvenile ovarian granulosa cell tumors (OGCTs) were markedly reduced. More recently, the somatic mutation p.Cys134Trp as recurring in adult OGCTs has been identified. This mutation may provide the tumor with either a striking proliferative potential or

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increased survival abilities. Moreover, it is proposed, that FOXL2 in OGCTs may act as a tumor suppressor gene. Besides FOXL2, other forkhead transcription factors can be involved in the etiology of cancer (Benayoun et al., 2010).

5.3.3. Transcription factors of Smad family GDF9 promotes both Smad 3 and Smad 4 expression and [3H]-thymidine uptake. by granulosa cells. This observation could be an indirect evidence, that that Smad 3,4 could be potentially involved in up-regulation of ovarian cell proliferation ( Mottershead et al., 2008).

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5.3.4. Other Transcription Factors The embryonic stem cell transcription factors SOX2, NANOG, and OCT3/4 are involved in the regulation of germ cell tumor growth and differentiation. The increased accumulation of these transcription factors in embryonal carcinomas were reported (Chang et al., 2009). Transcription factor p53 inhibits proliferation in normal (Sirotkin et al., 2008) and cancer (Naidu et al., 2007) ovarian cells. Overexpression of the signal transducer and activator of transcription 1 (STAT-1) decreased the accumulation of proliferationassociated MAPK/ERK1,2 but not that of PCNA (Benčo et al., 2009) (Fig.1). Transfection-induced overexpression of cAMP response element binding (CREB) in ovarian granulosa cells increased expression of proliferation markers suggesting up-regulation of this process by CREB (Sirotkin and Tandlmajerova, unpublished data). On the contrary, suppression of CREB inhibited proliferation of ovarian cancer cells (Linnerth et al., 2008). We have observed the stimulatory action of different isoforms/subunits of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) on proliferation of ovarian granulosa cells (Pavlova and Sirotkin, unpublished data).

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5.4. Transcription Factors Involved in Control of Ovarian Cell Apoptosis Analysis of FOXL2 mutations demonstrated the involvement of this transcription factor in the regulation of apoptosis, reactive oxygen species detoxification and inflammation processes (Moumné et al., 2008). Transfection of porcine granulosa cells by a gene construct encoding STAT1 promoted the expression of apoptosis-related marker Bax, but not of antiapoptotic Bcl-2 (Benčo et al., 2009) (Fig.1.). Blockade of STAT3 promoted expression of apoptosis marker (caspase 3) and inhibited anti-apoptotic bcl-Xl in ovarian cancer cells (Huang et al., 2008). Ovarian cancer is frequently associated with mutations in p53 expression (Corney and Nikitin, 2008). P53 is an inductor of apoptosis and authophagy in ovarian tumor cels (Jin, 2005). Overexpression of p53 increased expression of apoptosic marker in healthy ovarian granulosa cells in vitro (Sirotkin et al., 2008) and in vivo (Ghafari et al., 2009). Presence of apoptosis-related substances p53 and Bax in rabbit ovarian granulosa cells is demonstrated in Fig.2. Transfection-induced overexpression of CREB in ovarian granulosa cells increased expression of apoptosis markers suggesting up-regulation of this process by CREB (Sirotkin and Tandlmajerova, unpublished data). NFkB was reported to be potent inhibitor of apoptosis in ovarian granulosa (Xiao et al., 2002; Ren et al., 2007) and luteal (Telleria et al., 2004) cells. On the other hand, we have observed the stimulatory action of different isoforms/subunits of NFkB on some markers of apoptosis in ovarian granulosa cells (Pavlova and Sirotkin, unpublished data).

5.5. Transcription Factors Involved in Control of Ovarian Secretory Activity 5.5.1. Transcription Factors of Smad Family Knock-down of Smad4 in mice resulted disruption of steroidogenesis and increased levels of serum progesterone (Pangas et al., 2006). Smad3, but not Smad2, cooperated with GATA-4 in the transcriptional activation of the inhibin-alpha promoter. GATA-4, interacting with Smad3, is a cofactor for TGF-beta signalling to activate expression of inhibin-alpha in granulosa cells (Anttonen et al., 2006).

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5.5.2. Other Transcription Factors FOXL2 has been suggested to be involved in the regulation of cholesterol and steroid metabolism (Moumné et al., 2008). Overexpression of early growth response factor-1 (EGR-1) increased the levels of mRNA for prostaglandin G/H synthase-2, PG E synthase, PG E2 receptor, but not for cytochrome P450-side chain cleavage or cytochrome P450 aromatase in granulosa cultures. These observations suggest the importance of EGR-1 in control of ovarian prostaglandin and prostaglandin receptor, but not in steroid hormones biosynthesis (Sayasith et al., 2006). Transcription factors TATA binding protein, E2F and CAAT binding protein could be also involved in control of ovarian gene encoding aromatase catalyzing estrogen production (Sharma et al., 2009). Overexpression of STAT 1 promoted prostaglandin F and oxytocin, but not progesterone release by cultured granulosa cells (Benčo et al., 2009). Blockade of hypoxia-induced transcription factors (HIFs) reduced the expression of vascular endothelial growth factor A, a key factor controlling vascularization/angiogenesis during ovulation (Alam et al., 2009; Kim et al., 2009). Transformation-specific transcription factors (Ets) binding sites are present in promoter of cyclooxygenase-2, a key enzyme for prostaglandin synthesis. Addition of Etv5 increased the transcriptional activity of cyclooxygenase promoter. This demonstrates the involvement of Ets in control of ovarian prostaglandine synthesis and probably of others, prostaglandin-regulated ovarian functions (Eo et al., 2008). Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) can suppress catabolism of progesterone in rat luteal cells (Telleria et al., 2004), but did not affect progesterone release by human luteal cells (Gonzalez-Navarrete et al., 2007). Transfection of porcine granulosa cells with cDNA construct inducing overexpression of STAT-1 increased oxytocin and prostaglandin F, but not progesterone release (Benčo et al., 2009) (Fig. 1). Overexpression of p53 resulted in reduced progesterone and prostaglandin F secretion and increased oxytocin and prostaglandin E release by cultured porcine granulosa cells (Sirotkin et al., 2008) (Fig.3).

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Figure 1. The transfection-induced overexpression of STAT-1 affects basal and ghrelinFigure 1: The transfection-induced of STAT-1 basal and ghrelin-induced expression of marker of apoptosis induced expression of markeroverexpression of apoptosis baxaffects (immunocytochemistry) (a), proliferation bax (immunocytochemistry) (a), proliferation marker MAPK/ERK1,2 (immunocytochemistry) (b) and release of oxytocin marker MAPK/ERK1,2 (immunocytochemistry) (b) and release of oxytocin (RIA) (c) groups by of (RIA) (c) by cultured porcine granulosa cells. a) shows a significant (p