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COMPREHENSIVE GYNECOLOGY, EIGTH EDITION ISBN: 978-0-323-65399-2

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 List of Contributors

Arnold P. Advincula, MD, FACOG, FACS Anne R. Davis, MD, MPH Paola Alvarez Gehrig, MD
Levine Family Professor of Women’s Wyeth Ayerst Professor Professor & Chief
Health Obstetrics and Gynecology Division of Gynecologic Oncology
Vice-Chair, Department of Obstetrics & Columbia University Irving Medical Center University of North Carolina
Gynecology New York, New York Chapel Hill, North Carolina
Chief of Gynecologic Specialty Surgery,
Mary Segars Dolan, MD, MPH David M. Gershenson, MD
Sloane Hospital for Women
Associate Professor Professor
Columbia University
Gynecology and Obstetrics Gynecologic Oncology and Reproductive
New York, New York
Emory University Medicine
Jamie N. Bakkum-Gamez, MD Atlanta, Georgia University of Texas MD Anderson
Professor Cancer Center
Sarah K. Dotters-Katz, MD, MMHPE
Obstetrics and Gynecology Houston, Texas
Assistant Professor
Mayo Clinic
Obstetrics and Gynecology Jennifer Bushman Gilner, MD, PhD
Rochester, Minnesota
Duke University Assistant Professor
Genevieve Bouchard-Fortier, MD, Durham, North Carolina Obstetrics and Gynecology
FRCSC, MSc Duke University
Nataki C. Douglas, MD, PhD
Assistant Professor Durham, North Carolina
Associate Professor
University Health Network
Department of Obstetrics, Gynecology Laura J. Havrilesky, MD, MHSc
Division of Gynecologic Oncology
and Women’s Health Professor, Division of Gynecologic
Obstetrics and Gynecology University
Rutgers–New Jersey Medical School Oncology
of Toronto
Newark, New Jersey Obstetrics and Gynecology
Toronto, Ontario, Canada
Duke University
Sean C. Dowdy, MD
Anne Burke, MD, MPH Durham, North Carolina
Professor
Associate Professor
Obstetrics and Gynecology Cherie C. Hill, MD
Gynecology and Obstetrics
Mayo Clinic Assistant Professor
Johns Hopkins University
Rochester, Minnesota Gynecology and Obstetrics
Baltimore, Maryland
Emory University School of Medicine
Linda O. Eckert, MD
Leslie H. Clark, MD Atlanta, Georgia
Professor
Assistant Professor
Department of Obstetrics and Gynecology; Hye-Chun Hur, MD, MPH
Obstetrics and Gynecology, Division
Adjunct Professor Associate Professor
of Gynecologic Oncology
Department of Global Health Minimally Invasive Gynecologic Surgery
University of North Carolina
University of Washington Department of Obstetrics and
at Chapel Hill,
Seattle, Washington Gynecology
Chapel Hill, North Carolina
Columbia University Irving Medical
Michael Fialkow, MD, MPH
Robert L. Coleman, MD Center
Professor
Professor & Deputy Chair New York, New York
Obstetrics and Gynecology
Department of Gynecologic Oncology &
University of Washington School Anuja Jhingran, MD
Reproductive Medicine
of Medicine Professor
University of Texas MD Anderson
Seattle, Washington Radiation Oncology
Cancer Center
University of Texas MD Anderson
Houston, Texas Eric J. Forman, MD, HCLD
Cancer Center
Medical and Laboratory Director
Allan Covens, MD, FRCSC Houston, Texas
Department of Obstetrics and Gynecology
Head
Columbia University Irving Medical James M. Kelley III, BA, JD
Sunnybrook Health Science Center;
Center Managing Partner
Professor & Chair
Division of Reproductive Endocrinology Medical Malpractice
Division of Gynecologic Oncology
& Infertility Elk & Elk Co Ltd
Obstetrics and Gynecology University
New York, New York Cleveland, Ohio
of Toronto
Toronto, Ontario, Canada Michael Frumovitz, MD, MPH Anna C. Kirby, MD, MAS
Professor and Associate Chief Patient Assistant Professor
Deborah S. Cowley, MD
Experience Officer Obstetrics and Gynecology
Professor
Gynecologic Oncology and Reproductive University of Washington
Psychiatry and Behavioral Sciences
Medicine Seattle, Washington
University of Washington
University of Texas MD Anderson
Seattle, Washington
Cancer Center
Houston, Texas
v
vi List of Contributors

Jeffrey A. Kuller, MD James W. Orr, Jr., MD, FACS, FACOG David T. Rock, MD
Professor of Obstetrics and Gynecology Clinical Professor, Florida State College Director of Breast Surgery Fellowship
Division of Maternal-Fetal Medicine of Medicine 21st Century Oncology;
Duke University Medical Center Medical Director, Regional Cancer Breast Surgeon
Durham, North Carolina Center Lee Health Regional Breast Care
Chief of Surgical Oncology, GenesisCare Fort Myers, Florida
Eduardo Lara-Torre, MD, FACOG
Tallahassee, Florida
Vice Chair, Department of OBGYN Timothy Ryntz, MD
Section Chief, Academic Specialists in Amanda Padro, MS, CGC Assistant Professor
General OBGYN Prenatal Genetic Counselor Obstetrics and Gynecology
Carilion Clinic MFM OB/GYN Columbia University School of Medicine
Professor Duke University New York, New York
Department of OBGYN and Pediatrics Raleigh, North Carolina
Mila Pontremoli Salcedo, MD, PhD
Virginia Tech-Carilion School of
Natacha Phoolcharoen, MD Associate Professor
Medicine
Lecturer The Department of Obstetrics &
Roanoke, Virginia
Obstetrics and Gynecology Gynecology
Gretchen M. Lentz, MD, FACOG Faculty of Medicine, Chulalongkorn Federal University of Health Sciences/
Professor, Obstetrics and Gynecology University Bangkok Irmandade Santa Casa de Misericordia
Adjunct Professor, Urology Thailand; de Porto Alegre, Porto Alegre, Brazil;
Division Director, Urogynecology Visiting Scientist Visiting Assistant Professor
University of Washington Medical Gynecologic Oncology and Reproductive The Department of Gynecologic
Center Medicine Oncology and Reproductive Medicine
Seattle, Washington University of Texas MD Anderson University of Texas MD Anderson
Cancer Center Cancer Center
Roger A. Lobo, MD
Houston, Texas Houston, Texas
Professor, Obstetrics and Gynecology
Division of Reproductive Endocrinology Thomas M. Price, MD Gloria Salvo, MD
Columbia University Professor Medical Research
New York, New York Obstetrics and Gynecology Gynecologic Oncology and Reproductive
Duke University Medicine
Karen H. Lu, MD
Durham, North Carolina University of Texas MD Anderson
Chair and Professor
Cancer Center
Gynecologic Oncology and Reproductive Beth W. Rackow, MD
Houston, Texas
Medicine Associate Professor
University of Texas MD Anderson Obstetrics & Gynecology and Pediatrics Samith Sandadi, MD, MSc
Cancer Center Columbia University Medical Center Gynecologic Oncologist
Houston, Texas New York, New York Breast Surgeon
Clinical Assistant Professor
Vicki Mendiratta, MD Pedro T. Ramirez, MD
Florida State School of Medicine
Associate Professor Professor
Florida Gynecologic Oncology
Obstetrics and Gynecology Gynecologic Oncology & Reproductive
21st Century Oncology
University of Washington Medicine
Fort Myers, Florida
Seattle, Washington University of Texas MD Anderson
Cancer Center; Kathleen M. Schmeler, MD
Larissa A. Meyer, MD, MPH
Director Professor
Associate Professor
Minimally Invasive Surgical Research & Department of Gynecologic Oncology &
Gynecologic Oncology and Reproductive
Education Reproductive Medicine
Medicine
University of Texas MD Anderson The University of Texas MD Anderson
University of Texas MD Anderson
Cancer Center Cancer Center
Cancer Center
Houston, Texas; Houston, Texas
Houston, Texas
Editor in Chief
Judith A. Smith, BS, PharmD
Jane L. Miller, MD International Journal of Gynecological
Associate Professor
Associate Professor Cancer
Obstetrics, Gynecology and
Urology
Licia Raymond, MD Reproductive Sciences
University of Washington
Clinical Assistant Professor UTHealth-McGovern Medical School
Seattle, Washington
Obstetrics-Gynecology Houston , Texas;
Andra Nica, MD, MSc, FRCSC University of Washington Oncology Clinical Pharmacy Specialist
Clinical Fellow Seattle, Washington Pharmacy
Obstetrics and Gynaecology Memorial Hermann Hospital Cancer
Eleanor H. J. Rhee, MD
Division of Gynecologic Oncology Center
Assistant Professor
University of Toronto Houston, Texas
Division of Maternal Fetal Medicine
Toronto, Ontario, Canada
Obstetrics and Gynecology Pamela T. Soliman, MD, MPH
Jaclyn D. Nunziato, MD, MS Duke University Professor
Assistant Professor of Obstetrics and Gynecologic Oncology and Reproductive
Katherine Rivlin, MD, MSc
Gynecology Medicine
Assistant Professor
Department Obstetrics and Gynecology University of Texas MD Anderson
Obstetrics and Gynecology
Virginia Tech Carilion School of Cancer Center
The Ohio State University Wexner
Medicine Roanoke, Virginia Houston, Texas
School of Medicine
Roanoke, Virginia
Columbus, Ohio
 List of Contributors vii

Anil K. Sood, MD Jenna Turocy, MD Shannon N. Westin, MD, MPH

Professor and Vice Chair Reproductive Endocrinology and Associate Professor
Gynecologic Oncology & Reproductive Infertility Fellow Gynecologic Oncology and Reproductive
Medicine Obstetrics and Gynecology Medicine
University of Texas MD Anderson Columbia University University of Texas MD Anderson
Cancer Center New York, New York Cancer Center
Houston, Texas Houston, Texas
Fidel A. Valea, MD
Premal H. Thaker, MD, MSc Professor and Chair Zev Williams, MD, PhD
Professor and Director of Gynecologic Department of Obstetrics and Associate Professor and Division Chief
Oncology Clinical Research Gynecology Department of Obstetrics and
Department of Obstetrics and Division of Gynecologic Oncology Gynecology
Gynecology Virginia Tech Carilion School of Division of Reproductive Endocrinology
Washington University School of Medicine & Infertility
Medicine Roanoke, Virginia Columbia University Irving Medical
St. Louis, Missouri Center
Catherine H. Watson, MD
New York, New York
Mireille Truong, MD Gynecologic Oncology Fellow
Assistant Professor Obstetrics and Gynecology
Program Director, Fellowship in Duke University
Minimally Invasive Gynecologic Durham, North Carolina
Surgery
Cedars-Sinai Medical Center
 Preface

“Wisdom is not a product of schooling but of the lifelong attempt to the same chapters, although in two instances we have consolidated
acquire it.” chapters, combining vulvar and vaginal cancers, as well as combin-
Albert Einstein ing fallopian tube and peritoneal cancers with ovarian cancer. As
in the previous two editions, we have added several new coauthors
Having first been published in 1987, Comprehensive Gynecology is to continue to enhance the expertise necessary to maintain the
now in its eighth edition. And once again, it is appropriate to pay book’s high quality. Importantly, each of the chapters has been
tribute to the legacy of the original editors—Drs. William significantly updated.
Droegmueller, Arthur L. Herbst, Daniel R. Mishell, Jr., and We have provided the most important references in the body
Morton A. Stenchever—each of whom was a giant within our of the chapter, allowing the reader to have immediate access to
discipline and who had the wisdom and foresight to create a the source, rather than having to search for the reference. In ad-
textbook that has guided generations of gynecologists to make a dition, we have maintained a limited number of Key References
difference in the lives of women. at the end of each chapter and Suggested Readings, which are
At this writing, we are in the midst of the 2020 COVID-19 available online.
pandemic. “The Great Influenza” pandemic occurred a little over As in the prior edition, we have provided video content to
a century ago, and one of the scientists in that fight was Simon provide a more visual experience for the reader. New and better
Flexner, first Director of the Rockefeller Institute and brother of illustrations have also been added to assist in visual learning.
Abraham Flexner, author of the 1910 Flexner Report, which exam- Nearly every chapter has key points, which have been bundled
ined the state of American medical education. Thinking about together in an online synopsis of the entire book. This will allow
Flexner’s emphasis on medical education reform, Einstein’s rapid assessment of the content of each chapter for more in-
advice about the acquisition of wisdom, and the current attention depth reading of areas of greater interest, as well as provide key
to lifelong learning and self-assessment by the American Board of learning facts in all areas of gynecology.
Obstetrics and Gynecology, it is appropriate to introduce this We hope readers will enjoy this edition and learn as much as
latest edition of Comprehensive Gynecology, with the hope that it they can from this ever-evolving field in order to provide better
will be of value to practicing gynecologists, trainees in obstetrics health care for women.
and gynecology, and subspecialists alike. We would like to extend our gratitude to the Elsevier staff—
The doubling time of medical knowledge was estimated to be Sarah Barth, Senior Content Strategist; and Melissa Rawe,
50 years in 1950, 7 years in 1980, and 3.5 years in 2010. In 2020, Content Development Specialist—who have shepherded this
it is projected to be 0.2 years (73 days). Certainly, the field of gyne- entire process with extraordinary professionalism.
cology is no exception. Mastering complex surgical procedures, We would also like to thank our families, without whose
keeping abreast of the latest medical therapies for gynecologic con- support, patience, and encouragement this project could not have
ditions, grasping the advances and nuances of the electronic medical been accomplished.
record, and understanding the rapidly expanding field of molecular
biology and genetics as it relates to our specialty is challenging. David M. Gershenson, MD
Despite the doubling time of medical information, the con- Gretchen M. Lentz, MD
tributors and editors have made every effort to deliver the most Fidel A. Valea, MD
updated and relevant content. In this edition, we have maintained Roger A. Lobo, MD

ix
 Contents

PART I 16 Early and Recurrent Pregnancy Loss, 323

Basic Science Jenna Turocy, Zev Williams

1 Fertilization and Embryogenesis, 1 17 Ectopic Pregnancy, 342

Thomas M. Price, Fidel A. Valea Hye-Chun Hur, Roger A. Lobo

2 Reproductive Genetics, 21 18 Benign Gynecologic Lesions, 362

Jennifer Bushman Gilner, Eleanor H. J. Rhee, Amanda Padro, Mary Segars Dolan, Cherie C. Hill, Fidel A. Valea
Jeffrey A. Kuller
19 Endometriosis, 409
3 Reproductive Anatomy, 47 Arnold P. Advincula, Mireille Truong, Roger A. Lobo
Jaclyn D. Nunziato, Fidel A. Valea
20 Pelvic Organ Prolapse, Abdominal Hernias,
4 Reproductive Endocrinology, 76 and Inguinal Hernias, 428
Nataki C. Douglas, Roger A. Lobo Anna C. Kirby, Gretchen M. Lentz

5 Evidence-Based Medicine and Clinical 21 Lower Urinary Tract Function and

Epidemiology, 106 Disorders, 461
Catherine H. Watson, Fidel A. Valea, Laura J. Havrilesky Gretchen M. Lentz, Jane L. Miller

6 Medical-Legal Risk Management, 116 22 Anal Incontinence, 495

James M. Kelley III, Gretchen M. Lentz Gretchen M. Lentz, Michael Fialkow

23 Genital Tract Infections, 515

PART II Linda O. Eckert, Gretchen M. Lentz
Comprehensive Evaluation of the Women
24 Preoperative Counseling and Management, 543
7 History, Physical Examination, and Preventive Jamie N. Bakkum-Gamez, Sean C. Dowdy, Fidel A. Valea
Health Care, 127
Vicki Mendiratta, Gretchen M. Lentz 25 Perioperative Management of Complications, 559
Leslie H. Clark, Paola Alvarez Gehrig, Fidel A. Valea
8 Interaction of Medical Diseases and Female
Physiology, 140 26 Abnormal Uterine Bleeding, 594
Sarah K. Dotters-Katz, Fidel A. Valea Timothy Ryntz, Roger A. Lobo

9 Additional Considerations in Gynecologic PART IV

Care, 148 Gynecologic Oncology
Deborah S. Cowley, Anne Burke, Gretchen M. Lentz
27 Molecular Oncology in Gynecologic Cancer, 606
10 Endoscopy in Minimally Invasive Gynecologic Premal H. Thaker, Anil K. Sood
Surgery, 188
Licia Raymond, Gretchen M. Lentz 28 Principles of Radiation Therapy and Chemotherapy
in Gynecologic Cancer, 618
PART III Judith A. Smith, Anuja Jhingran
General Gynecology 29 Intraepithelial Neoplasia of the Lower Genital
11 Congenital Abnormalities of the Female Tract (Cervix, Vagina, Vulva), 637
Mila Pontremoli Salcedo, Natacha Phoolcharoen,
Reproductive Tract, 207
Kathleen M. Schmeler
Beth W. Rackow, Roger A. Lobo, Gretchen M. Lentz

12 Pediatric and Adolescent Gynecology, 221 30 Neoplastic Diseases of the Vulva and Vagina, 648
Michael Frumovitz
Eduardo Lara-Torre, Fidel A. Valea

13 Contraception and Abortion, 238 31 Malignant Diseases of the Cervix, 674

Anuja Jhingran, Larissa A. Meyer
Katherine Rivlin, Anne R. Davis

14 Menopause and Care of the Mature Woman, 255 32 Malignant Diseases of the Uterus, 691
Pamela T. Soliman, Karen H. Lu
Roger A. Lobo

15 Breast Diseases, 289 33 Malignant Diseases of the Ovary, Fallopian Tube,

Samith Sandadi, David T. Rock, James W. Orr Jr., and Peritoneum, 707
Fidel A. Valea Robert L. Coleman, Shannon N. Westin, Pedro T. Ramirez,
Gloria Salvo, David M. Gershenson

xi
xii Contents

34 Gestational Trophoblastic Disease, 754 38 Androgen Excess in Women, 810

Andra Nica, Geneviève Bouchard-Fortier, Allan Covens Roger A. Lobo

39 Polycystic Ovary Syndrome, 824

PART V Roger A. Lobo
Reproductive Endocrinology and Infertility
40 Infertility, 838
35 Primary and Secondary Dysmenorrhea, Roger A. Lobo
Premenstrual Syndrome, and Premenstrual
Dysphoric Disorder, 768 41 In Vitro Fertilization, 861
Vicki Mendiratta, Gretchen M. Lentz Eric J. Forman, Roger A. Lobo

36 Primary and Secondary Amenorrhea and Index, 873

Precocious Puberty, 781
Roger A. Lobo

37 Hyperprolactinemia: Evaluation and

Management, 801
Roger A. Lobo
 Video Contents

1 Fertilization and Embryogenesis 10 Endoscopy in Minimally Invasive Gynecologic

Thomas M. Price, Fidel A. Valea Surgery
Licia Raymond, Gretchen M. Lentz
1.1 Embryo Biopsy and Cell Extrusion
10.1 Transection of the Round Ligament and
3 Reproductive Anatomy Dissection of the Broad Ligament
Jaclyn D. Nunziato, Fidel A. Valea
3.1 Uterine Artery Dissection
3.2 Anatomy of Uterosacral Ligaments
3.3 Identification of the Course of the Ureter

xiii
 PART
I Basic Science

1 Fertilization and Embryogenesis

Thomas M. Price, Fidel A. Valea

KEY POINTS
• Oocyte meiosis is arrested in prophase I from the fetal period (sex-determining region Y) gene found on the short arm of
until a luteinizing surge (LH) preceding ovulation. With the the Y chromosome. SRY protein is a transcription factor and
LH surge, the oocyte completes meiosis I associated with a de- expression is unique to the Sertoli cell of the developing testis.
crease to 23 chromosomes with diploid (2N) DNA quantity SRY induces expression of another transcription factor, SOX9,
and extrusion of the first polar body. With fertilization, meiosis which is also obligatory for male sex differentiation. A loss of
II is completed with separation of sister chromatids resulting in function mutation of either SRY or SOX9 results in XY sex
23 chromosomes with haploid (1N) DNA content and extru- reversal in which genetic men are phenotypic women. Several
sion of the second polar body. genes regulate SRY/SOX9 expression including WT1 (Wilms’
• Implantation is a complex process necessitating hormones of tumor suppressor 1) and SF1 (steroidogenic factor 1). Although
estrogen and progesterone, cytokines such as growth factors ovarian formation can only occur in the absence of SRY/SOX9,
and interleukins along with prostaglandins. During implanta- there are unique genes necessary for development. FOXL2
tion extravillous trophoblast invade the endometrium to anchor encodes a transcription factor necessary for granulosa cell
the pregnancy and to remodel the spiral arteries to make the expansion. BMP15, located on the X chromosome, and GDF9
placenta a high-flow, low-resistance organ. Villous trophoblast on chromosome 5 encode growth factors expressed in oocytes
are in contact with maternal blood in the intervillous space for required for granulosa cell proliferation.
gas and nutrient transfer. • Renal and internal genital development are closely related.
• Human chorionic gonadotropin (hCG) is secreted by syncytio- Under the influence of testosterone, the primordial renal
trophoblast and functions to maintain steroid production by mesonephros (wolffian ducts) differentiate into the vas
the corpus luteum through interaction with the LH receptor. deferens, epididymis, and seminal vesicles, while the parameso-
Other functions may include promotion of angiogenesis in the nephric ducts (müllerian ducts) are suppressed because of the
uterus, myometrial relaxation, inhibition of immune interaction secretion and action of antimüllerian hormone (AMH), also
at the uteroplacental interface, stimulation of fetal testosterone known as müllerian Inhibitory Substance (MIS), by Sertoli cells.
production and mediation of hyperemesis through receptors in In the absence of MIS, the wolffian ducts regress and the
the brain. müllerian ducts differentiate into the fallopian tubes, uterus,
• Genetic sex is determined at the time of conception. and cervix.
Male differentiation is determined by expression of the SRY

Accompanying video for this chapter is available on These 700 to 1300 cells migrate to the germinal ridge by way of
ExpertConsult.com. the dorsal mesentery of the hindgut by ameboid action by 5 to
6 weeks. Oogenesis begins with the replication of the diploid
MEIOSIS, FERTILIZATION, IMPLANTATION, oogonia through mitosis to produce primary oocytes, reaching a
peak number of 600,000 (confidence interval [CI]: 70,000 to
EMBRYONIC DEVELOPMENT, AND SEXUAL 5,000,000) at 18 to 22 weeks of gestation. Through apoptosis, the
DIFFERENTIATION numbers decline to about 360,000 (CI: 42,000 to 3,000,000) at
Several areas of medical investigation have brought increased menarche (Wallace, 2010). As can be seen, there is a large
attention to the processes of fertilization and embryonic variance among individuals and a direct correlation between the
development, including teratology, stem cell research, immunoge- number of fetal oocytes and the age of menopause. The maximum
netics, and assisted reproductive technology (ART). The preim- rate of fetal apoptosis occurs between 14 and 28 weeks gestation.
plantation, implantation, and embryonic stages of development Accelerated apoptosis is seen in Turner syndrome resulting in few
in the human can now be studied because of the development of oocytes at birth.
newer techniques and areas of research. This chapter considers The meiotic process actually begins at 10 to 12 weeks
the processes of oocyte meiosis, fertilization and early cleavage, gestation and is the mechanism by which diploid organisms
implantation, development of the genitourinary system, and sex reduce their gametes to a haploid state so that they can recom-
differentiation. bine again during fertilization to become diploid organisms.
In humans this process reduces 46 chromosomes to 23 chromo-
some structures in the gamete. The haploid gamete contains
THE OOCYTE AND MEIOSIS only one chromosome for each homologous pair of chromo-
The oocyte is a unique and extremely specialized cell. The pri- somes, so that it has either the maternal or paternal chromosome
mordial germ cells in both males and females are large eosino- for each pair, but not both. Meiosis is also the mechanism
philic cells derived from endoderm in the wall of the yolk sac. by which genetic exchange is completed through chiasma
1
2 PART I Basic Science

and by the end of the second trimester of pregnancy, the majority

Relative Abundance of Germ Cell

of oocytes in the fetal ovaries have cytologic characteristics that

Types in Human Fetal Ovary

are consistent with the diplotene/dictyotene substages of pro-

Primordial Oogonia Oocytes undergoing phase I of meiosis I (the stage at which the oocytes are arrested
germ meiosis until ovulation) (Fig. 1.2).
cells Oocytes at
diplotene Meiosis is preceded by interphase I during which DNA repli-
cation occurs, thus transforming the diploid oogonia with a DNA
content of 2N to an oocyte with a DNA content of 4N. Meiosis
is defined in two stages. The first, known as the reduction division
(division I, or meiosis I), initiates in the fetal ovaries but is then
arrested and completed at the time of ovulation.
1 2 3 4 5 6 7 8 9 Meiosis I starts with prophase I (prophase includes leptotene,
Months Gestation zygotene, pachytene, and diplotene), which occurs exclusively
during fetal life and sets the stage for genetic exchange that en-
Fig. 1.1 Diagram of the different meiotic cell types and their propor-
sures genetic variation in our species (Fig. 1.3). More oocytes are
tions in the ovaries during fetal life. (Courtesy Edith Cheng, MD.)
found in the leptotene stage of prophase then in the other three
stages of zygotene, pachytene, and diplotene in the fetal ovary.
Leptotene is proportionately the most abundant of all the pro-
formation and crossing over (recombination) between homolo- phase I substages in early gestation. Cells in this meiotic phase are
gous chromosome pairs. Two meiotic cell divisions are required characterized by a large nucleus with fine, diffuse, string-like
to produce haploid gametes. In the human female, oogonia enter chromatin evenly distributed within the nucleus (Fig. 1.3A).
meiosis in “waves” (Fig. 1.1), that is, not all oogonia enter Chromatin of homologous pairs occupies “domains” and does not
meiosis at the same time. occur as distinct linear strands of chromosomes. The zygotene
Meiosis initiation is dependent on mesonephric-produced substage is defined by the initiation of pairing, which is character-
retinoic acid (Childs, 2011). Oocytes in the first substage of pro- ized by the striking appearance of the synaptonemal complex
phase, leptotene, are found in the human fetal ovaries as early as formation in some of the chromosomes (Fig. 1.3B). There is cyto-
10 weeks’ gestation. With increasing gestational age, greater logic evidence of chromosome condensation and linearization,
proportions of oocytes in later stages of meiosis may be observed, and the chromatin is seen as a fine, stringlike structure. The

3rd month 4th month 7th month 9th month

Dictyotene
(resting stage)

Mitosis and Up to Up to
first meiosis zygotene diplotene
MEIOSIS I

Birth

1st polar body Anaphase I Puberty

formation

Meiosis Oocytes
Ovulation continues mature
each cycle

Fertilization Degeneration
2nd polar body of polar bodies
MEIOSIS II

formation

diploid
egg pronucleus nucleus
Meiosis
complete sperm pronucleus

Fig. 1.2 Diagram of oocyte meiosis. For simplicity, only one pair of chromosomes is depicted. Prophase
stages of the first meiotic division occur in the female during fetal life. The meiotic process is arrested at the
diplotene stage (“first meiotic arrest”), and the oocyte enters the dictyotene stages. Meiosis I resumes at pu-
berty and is completed at the time of ovulation. The second meiotic division takes place over several hours in
the oviduct only after sperm penetration. (Courtesy Edith Cheng, MD.)
 CHAPTER 1 Fertilization and Embryogenesis 3

content but contain 23 chromosome structures, each containing

two closely held sister chromatids. One daughter cell, the oocyte, 1
receives the majority of the cytoplasm, and the other becomes the
first polar body. The polar body is located in the perivitelline
space between the surface of the oocyte (oolemma) and the zona
pellucida (ZP).
Meiosis II is rapid, with the oocyte advancing immediately to
metaphase II, where the sister chromatids for each chromosome are
aligned at the equatorial plate, held together by spindle fibers at the
A B centromere. With sperm penetration, meiosis II is completed
with extrusion of the second polar body yielding a haploid
oocyte (1N) that is entered by a haploid (1N) sperm (Fig. 1.4).

Crossover and Female Aneuploidy

Aneuploidy in embryos is the most common cause of miscar-
riage and certain chromosomal abnormalities in live births,
including Down syndrome (trisomy 21). The majority of the
time these originate from an abnormal oocyte, increasing with
age, and are more likely to affect chromosomes with short
p arms (acrocentric). These chromosome segregation errors
C D occur predominantly during meiosis I and are more common
in the oocyte compared with the sperm. This is associated
Fig. 1.3 Fetal ovary with fluorescent in situ hybridization. The first three with deficient formation of chiasma between homologous
images are meiotic cells from a 21-week fetal ovary. A, Fluorescent in chromosomes associated with DNA crossover (recombination)
situ hybridization (FISH) with a whole chromosome probe for chromo- sites. Defective sites lead to less tension between homologous
some X was completed to visualize the pairing characteristics of the X chromosomes, making segregation errors more likely as the
chromosome during leptotene. B, Zygotene. C, Pachytene. D, Image spindles (microtubules) attached to the kinetochore protein
of a meiotic cell from a 34-week fetal ovary that underwent dual FISH complex adjacent to the centromere pull chromosomes toward
with probes for chromosomes 13 (green signal) and 21 (red signal) to the centrioles (Wang, 2017).
illustrate the pairing characteristics of this substage of prophase in
meiosis I. (Courtesy Edith Cheng, MD.)
Oocyte Cryopreservation
The clinical importance of meiotic spindle integrity was evident
pachytene substage is the most easily recognizable period of the during the development of oocyte cryopreservation. Oocyte freezing
prophase and is characterized by clearly defined chromosomes is becoming more common for fertility preservation in women with
that appear as continuous ribbons of thick beadlike chromatin medical conditions, such as cancer, for which chemotherapy and/or
(Fig. 1.3C). By definition, this is the substage in which all homo- radiation therapy may result in ovarian failure, and in women of in-
logues have paired. In this substage the paired homologues are creasing reproductive age. The original technique for oocyte freezing
structurally composed of four closely opposed chromatids and are was referred to as slow freezing, which was subsequently replaced
known as a tetrad. The frequency of oocytes in pachytene in- by vitrification. Freezing involves removal of intracellular water so
creases with gestational age and peaks in the mid-second trimester that ice crystals will not form during freezing, which may disrupt
of pregnancy (about 20 to 25 weeks’ gestation). The diplotene organelles. With slow freezing, cryoprotectants such as dimethyl
substage is a stage of desynapsis that occurs as the synaptonemal sulfoxide (DMSO) and ethylene glycol are allowed to permeate the
complex dissolves and the two homologous chromosomes pull cell, replacing the water, as the oocyte is slowly cooled at 1°C to
away from each other. However, these bivalents, which are com- 2°C/min to –196°C and stored in liquid nitrogen. In contrast, vitrifi-
posed of a maternally and a paternally derived chromosome, are cation involves the use of higher concentrations of cryoprotectant
held together at the centromere and at sites of chiasma formation and very rapid cooling at 15,000°C to 30,000°C/min. With slow
that represent sites where crossing over has occurred (Fig. 1.3D). freezing there is a slow change from liquid to solid, whereas vitrifica-
In general, chiasma formation occurs only between chromatids of tion consists of immediate solidification of the cryoprotectant into a
homologous pairs and not between sister chromatids. Usually, one glasslike consistency. With human oocytes, vitrification causes
to three chiasma occur for each chromosome arm. Oocytes at this much less spindle damage, resulting in higher oocyte survival rates.
stage of prophase I constitute the majority of third-trimester fetal
and newborn ovaries. Diplotene merges with diakinesis, the last
substage of meiosis I, and is a stage of transition to metaphase,
lasting many years in the humans. FERTILIZATION AND EARLY CLEAVAGE
During puberty, folliculogenesis includes progression of In most mammals, including humans, the egg is released from
the follicle, consisting of the oocyte and granulosa cells from an ovary in the metaphase II stage (Fig. 1.5). When the egg
primordial to antral, which is characterized by granulosa cell enters the fallopian tube, it is surrounded by a cumulus of granu-
proliferation, development of gonadotropin receptors, and losa cells (cumulus oophorus) and intimately surrounded by a
expression of enzymes for sex steroid production (Baerwald, clear ZP. Within the ZP are both the egg and the first polar body.
2012). It takes approximate 85 days for a follicle to mature to the Meanwhile, spermatozoa are transported through the cervical
point of ovulation. There is no change in the chromosome stage mucus and the uterus and into the fallopian tubes.
during folliculogenesis. Although 20 to 200 million sperm may enter the vagina during
Meiosis I resumes with the surge of luteinizing hormone intercourse, only 1 in 25,000 will make it to the fallopian tubes
before ovulation completing metaphase, anaphase, and telophase. (Williams, 1993). This journey involves processes of capacitation,
The result is two daughter cells, which are diploid (2N) in DNA chemotaxis, hyperactivated motility, and acrosome reaction
4 PART I Basic Science

Fig. 1.4 Diagram of oocyte meiosis. For simplicity, only three pairs of chromosomes are depicted (1 to 4).
Prophase stages of the first meiotic division, which occur in most mammals during fetal life. The meiotic
process is arrested at the diplotene stage (“first meiotic arrest”), and the oocyte enters the dictyate stages
(5 to 6). When meiosis is resumed, the first maturation division is completed (7 to 11). Ovulation occurs usually
at the metaphase II stage (11), and the second meiotic division (12 to 14) takes place in the oviduct only after
sperm penetration. (From Tsafriri A. Oocyte maturation in mammals. In Jones RE, ed. The Vertebrate Ovary.
New York: Plenum; 1978. With permission of Springer Science and Business Media.)

(Fig. 1.6). Capacitation precedes all other changes and involves most plasma membrane bind to specific ZP glycoprotein
initial removal of cholesterol from the plasma membrane altering receptors (primarily ZP 3). These interactions are very species
the permeability and fluidity. This allows influx of calcium and specific. Human sperm can only bind to the ZP of human, ba-
bicarbonate, with many downstream effects, such as increased boon, and gibbon oocytes. Binding results in fenestrations form-
cyclic adenosine monophosphate (cAMP), protein tyrosine ing between the plasma membrane and the underlying acrosome
phosphorylation, and activation of protein kinases. A function of membrane, releasing enzymes, including acrosin (a serine prote-
capacitation is to allow localization of protein complexes in the ase), to locally degrade the ZP.
head of the sperm that will subsequently bind the ZP. Chemotaxis Because many sperm may initially bind the ZP, a mechanism
is shown by a greater number of sperm in the ampullary portion must be in place to prevent fertilization by more than one
of the fallopian tube containing a cumulus-oocyte complex (COC) sperm (polyspermia). With initial binding of the sperm mem-
compared with the side lacking a COC. In vitro, follicular fluid brane to the oolemma, a calcium-dependent release of cortical
acts as a chemoattractant, possibly because of progesterone, but granules occurs. Cortical granules are vesicles containing pro-
the exact responsible constituents of the fluid continue to be tein made during oogenesis and located in the periphery of the
debated (Eisenbach, 1999). Hyperactivated motility involves in- cell. Contents are released into the perivitelline space and
creased vigorous movement of the sperm to penetrate the cumu- modify ZP proteins and enlarge the perivitelline space to pre-
lus (granulosa) cells surrounding the oocyte and is most likely vent sperm entry. With sperm entry, the oocyte completes
caused by progesterone. A major action of progesterone is to in- its second meiotic division, casting off the second polar
crease calcium influx into the sperm, with multiple downstream body into the perivitelline space.
effects. Likely the progesterone concentration increases as the The majority of a single sperm enters the oocyte, and this is
sperm approaches the egg, resulting in more aggressive motility. indeed the case during intracytoplasmic sperm injection (ICSI) for
When the egg is reached, receptor complexes on the outer infertility. Only the centrioles and the nucleus survive, whereas
 CHAPTER 1 Fertilization and Embryogenesis 5

Posterior wall
of uterus 1
Blastocysts

Morula Eight-cell Four-cell Two-cell Zygote Oocyte

stage stage stage penetrated
by sperm

Follicle Oocyte
Secondary approaching in tube
Growing
follicle follicle maturity
Mature
follicle
Early primary
follicle Oocyte

Blood
vessels

Epithelium

Corpus albicans
Released oocyte
Mature corpus luteum
Ruptured follicle
Atretic (degenerating) follicle
Developing
Endometrium Connective tissue
corpus
Coagulated blood
luteum

Fig. 1.5 Summary of the ovarian cycle, fertilization, and human development during the first week. Stage 1 of
development begins with fertilization in the uterine tube and ends when the zygote forms. Stage 2 (days 2 to 3)
comprises the early stages of cleavage (from 2 to approximately 32 cells, the morula). Stage 3 (days 4 to 5)
consists of the free (unattached) blastocyst. Stage 4 (days 5 to 6) is represented by the blastocyst attaching to
the posterior wall of the uterus, the usual site of implantation. The blastocysts have been sectioned to show
their internal structure. (From Moore KL, Persaud TVN. The Developing Human: Clinically Oriented Embryology.
7th ed. Philadelphia: WB Saunders; 2003.)

mitochondria in the midpiece and tail are destroyed. The sperm factors. Importantly, teratogens acting at this point are usually
centrioles interact with !-tubulin from the oocyte to form a micro- either completely destructive or cause little or no effect. Twin-
tubule network for migration of pronuclei and subsequent separa- ning may occur by the separation of the two cells produced by
tion of chromosomes during the first mitosis (Schatten, 2009). Thus cleavage, each of which has the potential to develop into a
mitochondria are of maternal origin and centrioles are paternal. separate embryo. Twinning may occur at any stage until the
Early cell division (cleavage) is not synchronous and varies in formation of the blastocyst (blast) because each cell is totipo-
time (Fig. 1.7). Time intervals from two pronuclei to two cells, tent. Both genetic and environmental factors are probably in-
two cells to three cells, three cells to four cells, and four cells to volved in the causation of twinning.
five cells are 26 hours, 12 hours, 0.8 hours, and 14 hours, re-
spectively, as determined with time-lapse photography during
in vitro fertilization (IVF) (Meseguer, 2011). A significant
Morula and Blastula Stage: Early Differentiation
number of fertilized oocytes do not complete cleavage for a After fertilization the zygote (term for a fertilized egg) has a diam-
number of reasons, including failure of appropriate chromo- eter of 83 to 105 "m and undergoes rapid mitotic division to reach
some arrangement on the spindle, specific gene defects that the next stage of approximately 16 cells called a morula. The cells
prevent the formation of the spindle, and environmental of the zygote and early cleavage embryo are considered totipotent
 6 PART I Basic Science

Zona pellucida
Perivitelline space

Corona radiata
Cytoplasm of oocyte

Second meiotic metaphase

1 2 3
First polar body
4

Plasma membrane
A of oocyte

Sperm nucleus Acrosome Plasma Perforations in Plasma Enzymes Sperm in cytoplasm

containing containing membrane acrosome wall membrane breaking down of oocyte without its
chromosomes enzymes of sperm of oocyte zona pellucida plasma membrane

1 2
3

B
Fig. 1.6 Acrosome reaction and a sperm penetrating an oocyte. The detail of the area outlined in A is given
in B. 1, Sperm during capacitation, a period of conditioning that occurs in the female reproductive tract.
2, Sperm undergoing the acrosome reaction, during which perforations form in the acrosome. 3, Sperm
digesting a path through the zona pellucida by the action of enzymes released from the acrosome. 4, Sperm
after entering the cytoplasm of the oocyte. Note that the plasma membranes of the sperm and oocyte have
fused and that the head and tail of the sperm enter the oocyte, leaving the sperm’s plasma membrane
attached to the oocyte’s plasma membrane. (From Moore KL, Persaud TVN: The Developing Human:
Clinically Oriented Embryology, 7th ed. Philadelphia, WB Saunders, 2003.)