The IVF Guide. Copyrighted Material. Universal-Publishers.com

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1 The IVF Guide

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3 The IVF Guide What You Need to Know About Fertility, Infertility and Available Treatment Options Asst. Prof. Ahmet Ozyigit, PhD & Assoc. Prof. Savas Ozyigit, MD Universal Publishers Irvine Boca Raton

4 The IVF Guide: What You Need to Know About Fertility, Infertility and Available Treatment Options Copyright 2018 Ahmet Ozyigit and Savas Ozyigit. All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the publisher, except in the case of brief quotations embodied in critical reviews and certain other noncommercial uses permitted by copyright law. Universal Publishers, Inc. Irvine Boca Raton USA (pbk.) (ebk.) Typeset by Medlar Publishing Solutions Pvt Ltd, India Cover design by Ivan Popov Publisher s Cataloging-in-Publication Data provided by Five Rainbows Cataloging Services Names: Ozyigit, Ahmet, author. Ozyigit, Savas, author. Title: The IVF guide : what you need to know about fertility, infertility and available treatment options / Ahmet Ozyigit [and] Savas Ozyigit. Description: Irvine, CA : Universal Publishers, Includes bibliographical references. Identifiers: LCCN ISBN (pbk.) ISBN (ebook) Subjects: LCSH: Fertilization in vitro. Reproductive technology. Infertility, Male. Infertility, Female. Pregnancy--Popular works. BISAC: MEDICAL / Reproductive Medicine & Technology. HEALTH & FITNESS / Infertility. Classification: LCC RG135.O (print) LCC RG135 (ebook) DDC /0599--dc23.

5 Table of Contents About the Authors Foreword 1 Reproductive Physiology: An Overview Physiology of Female Reproduction Physiology of Male Reproduction 12 2 Infertility What is Infertility? Female Infertility Male Infertility Recurrent Pregnancy Loss and Miscarriage 42 3 Infertility Testing An Overview of Infertility Testing Initial Infertility Testing Female Infertility Testing Male Infertility Testing Extended Infertility Testing 74 vii ix

6 vi The IVF Guide 4 Choosing the Right Treatment The Basis of Fertility Treatments Clomiphene Citrate Intrauterine Insemination In Vitro Fertilization Third Party Conception 98 5 Failed Treatments and Moving Forward Failure to Obtain Viable Egg or Sperm Cells Total Fertilization Failure Implantation Failure New Advances in Assisted Reproductive Technology Pre-implantation Genetic Diagnosis Time-lapse Embryo Imaging Platelet-rich Plasma Stem Cell Therapy Traveling Abroad for Treatment 131 Glossary 135 Appendix 1: Sample Infertility Assessment Form 145

7 About the Authors Asst. Prof. Dr. Ahmet Ozyigit is a clinical embryologist with over a decade of experience in assisting patients with fertility treatments. Dr. Ozyigit, who is currently studying medicine, comes from an eclectic background with a bachelor s, master s, and Ph.D. in economics and a master s degree in clinical embryology. His passion for education and research is the foundation for his career as a physician, embryologist, researcher, and clinic manager. He currently holds a teaching position at the Mediterranean University of Karpasia and is the lead for clinical research at North Cyprus IVF Center. I believe that IVF is a multi-disciplinary field and no embryologist, gynecologist, or fertility specialist is in a position to see the whole picture. This is the reason I have dedicated my life to attaining the knowledge and skills necessary to make a real difference in people s lives. Ahmet Ozyigit

8 viii The IVF Guide Assoc. Prof. Dr. Savas Ozyigit is the first fertility specialist in North Cyprus and has been a pioneer in fertility treatments for over two decades. Dr. Ozyigit is an active member of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine. He has also conducted clinical studies and published several articles and books on gynecology, pregnancy, and infertility. Dr. Ozyigit is the recipient of numerous accolades, including awards for medical excellence, lifetime achievement, and service quality. He is currently the chief of surgery at North Cyprus IVF Center. It is through our patient-centered approach that we can design effective treatments. Listening to patients not only helps us make a diagnosis, but it also shows the patients that we care. A caring attitude makes a significant difference in the quality of services that we offer. We should never forget that we treat patients, not test results. Savas Ozyigit

9 Foreword The medical information contained in this book represents an amalgamation of prior knowledge, clinical experience, and other medical sources. References are provided at the end of each chapter. This book does not aim to diagnose, cure, or offer any treatment advice. The purpose of this book is to combine theoretical knowledge from the existing literature with practical knowledge from the authors own clinical experience. This guide book is intended for patients exploring their fertility treatment options as well as students researching the field of reproductive medicine. Although most of the facts stated in this book are backed by scientific research and clinical evidence, some portions reflect the authors opinions based on years of experience. Although reasonable efforts have been made to provide the most accurate information available, this field is rapidly changing, and the authors cannot always guarantee the accuracy of the material herein or its fitness to guide clinical decisions. We recommend that our readers do their own research before accepting any information as fact and certainly before making potentially life-changing decisions.

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11 1 Reproductive Physiology: An Overview 1.1 Physiology of Female Reproduction Every woman is born with a finite number of non-renewable oocytes (egg cells), which is known as her ovarian reserve. The fact that a woman is born with all the eggs she will ever have is crucial for understanding female fertility. An ovarian reserve can be described as the number of immature eggs (contained in small cysts called follicles) within the ovaries at any point in time. Evidence suggests that the ovarian reserve reaches its maximum level of 6 to 7 million follicles at sixteen weeks gestation. Thus, a woman s ovarian reserve is at its highest level before she is even born! The ovarian reserve slowly decreases, leaving about two million follicles at the time of birth, 1 and approximately half of these eggs remain dormant until a girl reaches puberty. Before puberty, these eggs exist in the ovaries as primary follicles with no potential for fertilization. The hormonal changes of puberty activate a physical change in the ovaries that allows ovulation to occur.

12 2 The IVF Guide Puberty represents a sequence of events that mark the initiation of reproductive capacity. A pea-sized organ in the brain called the pituitary gland is responsible for the hormonal changes of puberty. Hormones released by the pituitary gland known as gonadotropins (follicle stimulating hormone and luteinizing hormone) initiate physiological changes that result in the production of sex hormones (mainly estrogen) by the gonads. In turn, estrogen stimulates breast development and the maturation of the reproductive organs, including the vagina, ovaries, and uterus. Sexual maturity is reached upon the completion of these changes. A girl s menstrual cycle also begins during puberty. A menstrual cycle consists of synchronized physiological changes in the ovaries and uterus that enable a girl or woman to become pregnant. During a menstrual cycle, the changes that occur in the ovaries are called the ovarian cycle and the changes that occur in the uterus are called the uterine cycle. These two cycles, working in harmony, ensure that the uterus is suitable for pregnancy following the release of an oocyte from the ovaries. The first occurrence of menstruation is called menarche, and the cessation of menstruation is called menopause. The average age for menarche is about 12 years, and the average age for menopause is about 51 years. Thus, a woman will have about 39 years of fertility and will menstruate about 468 times during her lifetime. Although several follicles mature inside a woman s ovaries each month, only one will reach the stage of ovulation. Thus, if a woman menstruates 468 times over her lifetime, only 468 out of the 2 million follicles she is

13 Reproductive Physiology: An Overview 3 born with will reach ovulation. Statistically speaking, each follicle has a 0.02% chance of reaching ovulation and potentially being fertilized. As a woman s ovarian reserve declines, so does her probability of becoming pregnant. The following diagram shows the number of follicles that an average woman has in her ovaries throughout her fertile years: Number 100,000 10,000 1, Age FADDY & GOSDEN, 1992 Figure 1: Average ovarian reserve by age. Source: Faddy M, Gosden R, Gougeon A, Richardson S, Nelson J. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Human Reproduction. 1992;7(10): A woman loses around 1,000 follicles a month, which is more than 10,000 follicles a year. Therefore, a girl who has 500,000 ovarian follicles at the start of puberty will have less than 1,000 follicles by the age of 48. Each month, only

14 4 The IVF Guide one follicle will ovulate and 1,000 follicles will go to waste. Unfortunately, there is not much that can be done to stop this phenomenon. We still do not fully understand why follicles become activated for ovulation. We only know that one follicle reaches ovulation in a given month and the rest are destined to die. Although certain environmental factors can increase the rate of follicular death, there is currently no available technology to prevent these unused follicles from dying. Certain lifestyle factors, such as cigarette smoking, have been linked to a decline in ovarian reserves. Genetic conditions and environmental factors may also contribute to the premature depletion of a woman s ovarian reserve. Although developments in medicine and reproductive technology have improved a woman s chance of becoming pregnant as her ovarian reserve declines, we are still limited by the laws of nature. From fetal life to menarche The ovaries, which are the primary female reproductive organs, are where oocyte (egg cell) development occurs. Oogenesis, the process of oocyte development, starts during fetal development and continues until menopause. There are two main cell types in our bodies: autosomal cells and gametes. Most of the cells in our bodies are autosomal, which undergo asexual reproduction (i.e., they divide and replicate without fusing with another cell). This process of asexual cell replication is called mitosis. During mitosis, a single cell copies itself into two genetically identical daughter cells. Mitosis is a normal part of human

15 Reproductive Physiology: An Overview 5 development and is the process by which the body replaces damaged or dead cells. Gametes are the cells involved in sexual reproduction and include sperm cells and egg cells. Meiosis is the type of cell division that produces gametes in the gonads. During meiosis, a parent cell produces two daughter cells that each contain half of the genetic material (i.e., each gamete contains 23 chromosomes instead of the normal 46). After fertilization, the resulting embryo will have 46 chromosomes (23 from the sperm cell and 23 from the egg cell). During oogenesis, immature oocytes undergo both mitosis and meiosis. Mitosis is responsible for expanding the ovarian reserve during fetal development. Through mitosis, the ovarian reserve reaches a population of 7 million oogonia (immature female gametes). Meiosis then occurs in two stages, the first of which takes place during the second trimester of fetal development. During this stage, the oogonia mature into primary oocytes, which will remain dormant until puberty. Figure 2 shows the stages of oogenesis. Once a woman reaches puberty, she will ovulate approximately once a month, at which point an oocyte becomes capable of fertilization. The average menstrual cycle lasts 28 days, during which many physical changes take place within the ovaries. Understanding these changes is crucial for understanding infertility, how in vitro fertilization (IVF) works, and why treatment protocols often differ from patient to patient. All of our advances in the field of reproductive medicine are essentially efforts to mimic natural human physiology.

16 6 The IVF Guide 2n Oogonium Mitosis Before birth After puberty Polar body Polar body 1n 1n The beginning of a menstrual cycle is marked by menstruation, the shedding of the lining of the uterus. Menstruation is commonly referred to as a woman s period. After menstruation, there are significant physiological changes in the ovaries and uterus, which are initiated and regulated by hormones from the brain. The first two weeks of a menstrual 2n 1n 1n 2n Primary oocyte (arrests in prophase I) Meiosis continues Secondary oocyte (arrests in metaphase II) Ovulation, sperm entry Meiosis, fertilization Fertilized Egg Figure 2: The stages of oogenesis. n represents 23 chromosomes. Source: Gametogenesis (Spermatogenesis and Oogenesis). Boundless. Boundless Biology.

17 Reproductive Physiology: An Overview 7 cycle are called the follicular phase, which is marked by the growth and development of follicles. The follicular phase ends when the dominant follicle ripens and ovulates. Ovulation usually takes place around day 14 of the menstrual cycle, which is halfway through a 28-day cycle. Immediately following ovulation, the second half of the menstrual cycle begins, which is called the luteal phase. This phase is marked by increased progesterone production, which helps prepare the uterus for a potential pregnancy. Thus, the luteal phase involves changes in uterine conditions rather than ovarian activity. Figure 3 shows the hormonal Body temperature Ovarian cycle Hormone levels Growing follicle Menstrual cycle Ovulation Ovulation Corpus luteum 37 C 36 C Hormone: Progesterone Estrogen LH FSH Figure 3: The ovarian cycle. Source: Designua. Menstrual cycle, increase and decrease of the hormones. Photograph. Shutterstock.

18 8 The IVF Guide changes and the stages of follicular growth and development that take place during a menstrual cycle. At the beginning of a menstrual cycle (the follicular phase), the follicles are still very small and release only small amounts of estrogen. Follicle stimulating hormone (FSH), which stimulates follicular growth, is the only hormone that is produced at relatively high levels during the follicular phase. As follicles become larger, they secrete greater amounts of estrogen. The increased production of estrogen is due to a special enzyme called aromatase, which is activated by high levels of FSH. Around day 7 or 8 of the menstrual cycle, there is a sharp increase in estrogen release in response to follicular changes, which signals the pituitary gland to slow down its release of FSH. This type of signal is known as negative feedback. Around day 8 or 9 of the menstrual cycle, while the level of estrogen continues to rise, the level of FSH begins to fall. During this time, another negative feedback hormone called inhibin is released by granulosa cells (the cells that surround follicles). Inhibin is another negative feedback signal that causes the pituitary gland to decrease the release of FSH. The level of estrogen continues to rise until there is a surge in the release of luteinizing hormone (LH), another hormone released by the pituitary gland. This LH surge is only possible when the dominant follicle reaches at least 15 mm in size and releases a critical level of estrogen. The LH surge causes specific changes in the granulosa cells surrounding the follicle and triggers an increase in the production of progesterone. The increased level of LH and progesterone initiates a series of events that leads to ovulation. Once ovulation takes

19 Reproductive Physiology: An Overview 9 place, the mature oocyte (egg) is released from the follicle and moves into the fallopian tube. This is where fertilization takes place if sperm is present (either through sexual intercourse or artificial insemination). As shown in Figure 3, the level of FSH increases again just prior to ovulation. At this stage during a menstrual cycle, the elevated estrogen level induces a very short-lived positive feedback response that increases the level of FSH. The mechanism underlying this positive feedback is still not well understood, but some believe that this brief increase in FSH is needed to recruit the next cohort of follicles for ovulation if fertilization does not occur. Once the mature egg has been released from the follicle at ovulation, the follicle becomes a temporary hormonereleasing structure known as the corpus luteum. The corpus luteum is responsible for estrogen and progesterone production during the early days of pregnancy. In the absence of a pregnancy, the corpus luteum degenerates. In some cases, the corpus luteum does not immediately degenerate and may remain in the ovary for a short period of time. However, in most cases, the corpus luteum cyst disappears within 1 to 3 months. When ovulation occurs, a woman s body temperature temporarily rises by approximately half a degree Celsius. This change in temperature is caused by the increased level of progesterone released from the corpus luteum. Many women who are trying to become pregnant monitor their body temperature on a daily basis to help with the timing of intercourse.

20 10 The IVF Guide While all of these hormonal changes are happening, visible physiological changes are also taking place in the uterus, which is called the uterine cycle. Despite being very small, the uterus has an extraordinary capacity to expand during pregnancy. Figure 4 shows the anatomical features of the female reproductive system. The two ovaries are connected to the uterus via the fallopian tubes. The fimbriae help move the ovulated oocyte into the fallopian tube, where fertilization occurs. The uterine wall comprises three distinct layers. The outermost layer is known as the perimetrium. The middle layer is known as the myometrium, which is the muscular layer of the uterine wall. The innermost layer of the uterine wall is called the endometrium. The endometrium is the layer where an embryo Fallopian tube Uterus Fundus Uterine tube Ovary Fimbriae Vagina Endometrium Myometrium Cervix Figure 4: The female reproductive system. Source: Suwin. Female reproductive system. Photograph. Shutterstock.

21 Reproductive Physiology: An Overview 11 implants at the start of a pregnancy. For implantation to occur, the conditions of the endometrium must be favorable. In a given menstrual cycle, the uterus develops thick, vascular endometrial tissue in order to provide support and nutrition for the implanting embryo. If a pregnancy occurs, then the endometrial wall remains thick to support the implanted embryo. If a pregnancy does not occur, then the endometrial wall breaks down and is shed as a bloody discharge during menstruation. The uterine cycle is shown in Figure 5. As with the ovarian cycle, the uterine cycle is also influenced by the interaction of various hormones from the brain Hormone levels Uterine cycle LH FSH Estrogen Progesterone Menses Proliferative phase Menstrual cycle Ovulation Secretory phase Premenstrual phase Day of menstrual cycle Figure 5: The uterine cycle. Source: Designua. Menstrual cycle: Menstruation, Follicle phase, Ovulation and Corpus luteum phase. Photograph. Shutterstock.

22 12 The IVF Guide and ovaries. There are four distinct phases of the uterine cycle. The first phase is menstruation, wherein the endometrial lining is shed as a bloody discharge. This bloody flow continues until the endometrium returns to its baseline thickness. Meanwhile, the ovaries prepare follicles for ovulation. The release of estrogen by the growing follicle prepares the ovaries for ovulation and stimulates the thickening of the endometrial wall. Initially, the estrogen helps thicken the endometrial wall by allowing for glandular formations. Estrogen also increases the number of progesterone receptors on the endometrium, thereby sensitizing the endometrium to progesterone. Thus, after ovulation, the increased level of progesterone can further increase the thickness of the endometrium and maintain favorable conditions for embryo implantation should fertilization occur. In the absence of fertilization, the endometrial lining is shed, causing another menstrual cycle to begin. During an IVF treatment, the goal is to mimic this physiological sequence of events and prepare the body for a successful pregnancy. A thorough understanding of female reproductive physiology is key to designing an effective fertility treatment regimen. 1.2 Physiology of Male Reproduction Due to the complexity of the female reproductive system and because the female system is responsible for both achieving and maintaining a pregnancy until birth, there are more

23 Reproductive Physiology: An Overview 13 opportunities for things to go wrong. Nevertheless, male infertility is also quite common. According to the American Society for Reproductive Medicine (ASRM), the male partner is either the sole cause or a contributing factor in 30 to 40% of couples suffering from infertility. 2 Male reproductive failure is often due to azoospermia, which is the total absence of sperm cells in the ejaculate. We will discuss azoospermia in depth in Chapter 2. In this section, we will highlight the most important elements of male reproductive physiology, focusing on the production and maturation of sperm cells (spermatogenesis). Like women, men reach their reproductive capacity at the onset of puberty. Each of the various organs of the male reproductive system has a specific role in spermatogenesis. The complete cycle of spermatogenesis takes about 65 to 70 days from start to finish. Thus, an immature sperm cell requires 65 to 70 days to undergo mitosis, meiosis, and be transported into the ejaculate. Many men modify their diet and lifestyle immediately before undergoing fertility treatment; however, such lifestyle modifications should begin at least two months prior to starting fertility treatment due to the duration of spermatogenesis. The duration of spermatogenesis is also important in the context of a febrile illness. Clinical research has shown that men who experience a fever of 39 C (102.2 F) or higher for three or more days can have serious impairment of their reproductive function for up to four months. 3 This is important to keep in mind when interpreting sperm analysis reports. To assess male reproductive function, at least two sperm tests

24 14 The IVF Guide should be performed three months apart to account for temporary reproductive impairment due to fever or other causes. Figure 6 illustrates the anatomical structures involved in male reproduction. Spermatogenesis is the process by which immature sperm cells (spermatogonia) become mature sperm cells (spermatozoa). There are many similarities as well as striking differences between oogenesis and spermatogenesis. The main differences are the reserves and the time of gamete production. For women, there is no further production of oocytes after birth. However, new sperm cells are being produced throughout a man s reproductive lifespan, which is why men have a longer period of fertility than women. However, men do experience a decline in their reproductive function with age. Urethra Penis Bladder Seminal vesicle Prostate gland Ejaculatory duct MALE REPRODUCTIVE SYSTEM Urethra Vas deferens Epididymis Scrotum Testicle Figure 6: Overview of male reproductive organs. Source: Alextian, R. Male reproductive system. Photograph. Shutterstock.

25 Reproductive Physiology: An Overview 15 During both oocyte and sperm cell development, gametes undergo mitosis and meiosis. Similar to oocytes, sperm cell populations grow via mitosis, and they lose half of their chromosomal content via meiosis. A detailed discussion of mitosis and meiosis is beyond the scope of this book, yet it is worth mentioning that successive mitotic and meiotic divisions are responsible for different stages of sperm maturation. Once a sperm cell becomes a spermatid, it will mature without undergoing any further cell division. Figure 7 illustrates the different stages of sperm maturation. The epididymis is a highly convoluted duct behind the testis that is the site of sperm maturation (Fig. 6). The epididymis also helps transport the sperm into the vas deferens. The vas deferens is the structure that transports mature sperm into the urethra. The ejaculatory duct releases sperm along with secretions produced by the seminal vesicles. These secretions enable the sperm to move within the female reproductive system and to fertilize the egg. These secretions also help protect ejaculated sperm from the acidic environment of the vaginal tract. The path for sperm release during sexual intercourse is long and requires cooperation between several different structures of the male reproductive tract. As previously mentioned, men continue to produce sperm cells until very late in life. One man reportedly fathered a child at the age of 96. However, evidence suggests that a man s ability to father a child declines with age and the incidence of genetic abnormalities in the offspring increases with both paternal and maternal age. Thus, paternal age can