Molecular Biology of the Female Reproductive System

453 Pages·1994·9.428 MB·English

by  J. K. Findlay (Eds.)

Molecular Biology
of the Female
Reproductive System
Edited by
J. K. Findlay
Prince Henry's Institute of Medical Research
Clayton, Victoria
Australia
ACADEMIC PRESS
A Division of Harcourt Brace & Company
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This book is printed on acid-free paper. @
Copyright © 1994 by ACADEMIC PRESS, INC.
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Library of Congress Cataloging-in-Publication Data
Molecular biology of the female reproductive system / edited by
J.K. Findlay.
p. cm.
Includes bibliographical references and index.
ISBN 0-12-256365-4 (hardcover)
1. Generative organs, Female-Molecular aspects. 2. Generative
organs, Female—Cytology. 3. Human reproduction—Molecular aspects.
I. Findlay, Jock K.
[DNLM: 1. Reproduction-physiology. 2. Sex Hormones-physiology.
3. Placental Hormones-physiology. WQ 205 C393 1994]
QP259.C46 1994
612.6'2~dc20
DNLM/DLC
for Library of Congress 93-30113
CIP
PRINTED IN THE UNITED STATES OF AMERICA
94 95 96 97 98 99 BC 9 8 7 6 5 4 3 2 1
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Eli Y. Adashi (83), Departments of Obstetrics/Gynecology and Physiology,
University of Maryland School of Medicine, Baltimore, Maryland 21201
Russell V. Anthony (395), Departments of Animal Sciences and Biochemis­
try, University of Missouri-Columbia, Columbia, Missouri 65211
Gustavo Ballejo (345), Department of Pharmacology, Faculdade de Medici-
na, Universidade de Sao Paulo, Ribreirao Preto, Brazil
Carol J. Belfiore (259), Department of Molecular Biology, University of
Wyoming, Laramie, Wyoming 82071
Timothy D. Braden (259), Department of Zoology, Oklahoma State Univer­
sity, Stillwater, Oklahoma 74078
David A. Clark (329), Departments of Medicine, Obstetrics and Gynecol­
ogy, and Pathology, Molecular Immunology-Virology Program, McMas-
ter University, Faculty of Health Sciences, Hamilton, Ontario, Canada
L8N 3Z5
Nava Dekel (207), The Department of Hormone Research, The Weizmann
Institute of Science, Rehovot 76100, Israel
Michelle Demeter-Arlotto (129), The Cecil H. and Ida Green Center for
Reproductive Biology Sciences, and the Departments of Obstet­
rics/Gynecology and Biochemistry, The University of Texas South­
western Medical Center, Dallas, Texas 75235
Gregory F. Erickson (39, 101), Department of Reproductive Medicine, Uni­
versity of California at San Diego, School of Medicine, La Jolla, California
92093
Stephen G. Hillier (1), Reproductive Endocrinology Laboratory, Depart­
ment of Obstetrics and Gynaecology, University of Edinburgh Centre for
Reproductive Biology, Edinburgh EH3 9EW, United Kingdom
Margaret M. Hinshelwood (129), The Cecil H. and Ida Green Center for
Reproductive Biology Sciences, and the Departments of Obstet­
rics/Gynecology and Biochemistry, The University of Texas South­
western Medical Center, Dallas, Texas 75235
XV
xvi Contributors
Arye Hurwitz (83), Departments of Obstetrics/Gynecology and Physiol­
ogy, University of Maryland School of Medicine, Baltimore, Maryland
21201
Ehud Kokia (83), Departments of Obstetrics/Gynecology and Physiology,
University of Maryland School of Medicine, Baltimore, Maryland 21201
Nicholas Ling (101), Neuroendocrine Biosciences, Inc., La Jolla, California
92037
X.-J. Liu (101), Department of Molecular Endocrinology, Whittier Institute
for Diabetes and Endocrinology, La Jolla, California 92037
Denis A. Magoffin (39), Department of Obstetrics and Gynecology,
Cedars-Sinai Medical Center, Los Angeles, California 90048
Kelly E. Mayo (153), Department of Biochemistry, Molecular Biology, and
Cell Biology, Northwestern University, Evanston, Illinois 60208
Gary D. Means (129), Fred Hutchinson Cancer Research Center, Basic Sci­
ences Division, Seattle, Washington 98104
Liam J. Murphy (345), Departments of Internal Medicine and Physiology,
Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Can­
ada R3E 0W3
Ewa Muzikova (329), Molecular Immunology-Virology Program, McMas-
ter University, Faculty of Health Sciences, Hamilton, Ontario, Canada
L8N 3Z5
Akira Nakatani (101), Department of Pathology, Nagasaki University
School of Medicine, Nagasaki 852, Japan
Colin D. Nancarrow (289), Division of Animal Production, CSIRO, Pros­
pect, New South Wales 2148, Australia
Gordon D. Niswender (259), Animal Reproduction and Biotechnology
Laboratory, Department of Physiology, Colorado State University, Fort
Collins, Colorado 80523
Ok-Kyong Park-Sarge (153), Department of Physiology, University of Ken­
tucky Medical School, Lexington, Kentucky 40536
Jeff A. Parrott (67), Reproductive Endocrinology Center, University of Cali­
fornia at San Francisco, San Francisco, California 94143
R. Michael Roberts (395), Departments of Animal Sciences and Biochemis­
try, University of Missouri-Columbia, Columbia, Missouri 65211
Eeva-Marja Rutanen (379), Department of Obstetrics and Gynecology,
Helsinki University Central Hospital, SF-00290 Helsinki, Finland
Lois A. Salamonsen (289), Prince Henry's Institute of Medical Research,
Clayton, Victoria 3168, Australia
Markku Seppala (379), Department of Obstetrics and Gynecology, Hel­
sinki University Central Hospital, SF-00290 Helsinki, Finland
Contributors xvii
Shunichi Shimasaki (101), Department of Molecular Endocrinology, Whit-
tier Institute for Diabetes and Endocrinology, La Jolla, California 92037
Evan R. Simpson (129), The Cecil H. and Ida Green Center for Reproduc­
tive Biology Sciences, and the Departments of Obstetrics/Gynecology
and Biochemistry, The University of Texas Southwestern Medical Center,
Dallas, Texas 75235
Michael K. Skinner (67), Reproductive Endocrinology Center, University
of California at San Francisco, San Francisco, California 94143
Alex Tsafriri (207), The Bernhard Zondek Hormone Research Laboratory,
The Department of Hormone Research, The Weizmann Institute of Sci­
ence, Rehovot 76100, Israel
Preface
Our understanding of the control of female reproduction has advanced
significantly in the past decade. Thus, the purpose of this book is twofold:
First, to show how the techniques of cellular and molecular biology have
led to this increase in knowledge and second, to review the autocrine,
paracrine, and endocrine systems controlling reproductive processes in the
female. With chapters by recognized leaders in the field, this book will be
of primary interest to students and researchers working in biomedical and
animal research. It will also be of interest to specialist medical and veterin­
ary practitioners, toxicologists, biologists, and teachers as a way of updat­
ing their knowledge.
The chapters focus on the ovary and uterus, including the interaction
between the developing trophectoderm of the blastocyst and the endo­
metrium. Chapters on the ovary include hormonal control of folliculo­
genesis and luteal function, cell-cell interactions in the follicle and the roles
of cytokines in regulating steroid and protein hormone production, and an
update on endocrine receptors and the mechanisms involved in ovulation.
The cell biology of the oviduct and uterus is reviewed, and there are chap­
ters on migratory cells and paracrine regulation in the endometrium. The
final chapter discusses the recent data on hormones of the trophectoderm
and placenta. The authors pay particular attention to the application of
cellular and molecular approaches to understanding control of the repro­
ductive processes and have provided extensive reference lists at the end of
each chapter for follow up.
This book differs from others in this field in both its focus and content
and, together with the previously published volume Molecular Biology of the
Male Reproductive System, edited by David de Kretser, will provide the read­
er with an extensive catalog of knowledge of the control of reproductive
processes at the cellular and molecular levels.
I extend my thanks to the authors for giving their valuable time to write
the excellent contributions, to my secretary, Faye Coates, and to Academic
Press for helping to produce the book.
Jock Findlay
xix
1
Hormonal Control of
Folliculogenesis and
Luteinization
STEPHEN G. HILLIER
I. Introduction
During each menstrual cycle, human ovaries sequentially synthesize
and secrete estradiol-;^ (estradiol) and progesterone-steroid hormones
that coordinate the function of the entire female reproductive system. In­
creased estradiol secretion characterizes the follicular phase of the cycle,
reflecting the specialized endocrine function of the preovulatory follicle.
After ovulation, the follicle luteinizes and secretes mainly progesterone at
rates mirroring the development and regression of the corpus luteum dur­
ing the luteal phase. This chapter surveys the major endocrine and para­
crine mechanisms that give rise to these processes and discusses the practi­
cal implications for more efficient and effective use of exogenous
gonadotropins to stimulate ovarian function in infertile women.
II. Control of Follicular Growth
A. The Ovarian Cycle
The human ovarian cycle lasts approximately 28 days and encom­
passes preovulatory follicular development (10-14 days), ovulation, and
the functional lifespan of the corpus luteum (12-15 days). Peripheral plas­
ma sex steroid, gonadotropin, and inhibin levels throughout the menstrual
cycle are illustrated in Figure 1.
Molecular Biology of the Female Reproductive System
Copyright © 1994 by Academic Press, Inc. All rights of reproduction in any form reserved. 1
2 Stephen G. Hillier
ESTRADIOL (pmol/l) A
INHIBIN (U/l) · PROGESTERONE (nmol/l) ο
Γ 80
1600 Η
1200 Η
800 Η
400 Η h 20
J
0
-15 -10 -5 0 5 10 15
DAY RELATIVE TO LH SURGE
FIGURE 1 Serum levels of estradiol, progesterone, and inhibin during the human menstrual
cycle. Data redrawn from McLachlan et al. (1990) with permission.
B. Preovulatory Follicular Development
The follicle destined to ovulate grows during the follicular phase of the
cycle, increasing in diameter from ~5 mm to >20 mm and becoming the
major ovarian source of secreted estrogen. This estrogen secretory stage
follows a programmed sequence of cell growth and differentiation in the
follicle wall that terminates in ovulation and transformation of the follicle
into a corpus luteum. The entire sequence of events depends upon primary
(endocrine) stimulation of the ovaries by the gonadotropins, follicle-
stimulating hormone (FSH) and luteinizing hormone (LH), underpinned
by local (paracrine and autocrine) levels of control emanating from within
the follicle itself.
Multiple immature antral follicles that are potentially able to undergo
preovulatory development are usually present in the ovaries at the begin­
ning of each normal menstrual cycle. These incipient preovulatory follicles
comprise a fluid-filled antral cavity surrounded by inner granulosa (to
which the cumulus-enclosed secondary oocyte is attached) and outer thecal
cell layers separated by a lamina basalis. Tonic stimulation of the ovaries by
both FSH and LH is necessary for follicles to achieve this intermediate stage
of development, but "recruitment" to the preovulatory stage of develop­
ment requires additional stimulation by FSH (Figure 2). By the midfollicular
phase, the follicle destined to ovulate will have grown to about 10 mm in
diameter and will be recognizable as the largest healthy follicle in either
ovary (Gougeon and Lefevre, 1983). Thereafter, during the second half of
the follicular phase, estrogen synthesis in this dominant follicle becomes
1 Hormonal Control of Folliculogenesis and Luteinization 3
FIGURE 2 Development-dependent stages in selection of the preovulatory follicle in the
human menstrual cycle. Recruitment: Blood FSH levels rise and stimulate the proliferation
and functional differentiation of granulosa cells in multiple immature follicles, including
induction of LH receptors and aromatase activity. Tonic stimulation by LH maintains thecal
androgen synthesis in these follicles. The follicle that will next ovulate is that which is most
responsive to FSH (i.e., that with the lowest FSH "threshold"). Dominance: By midfollicular
phase, the preovulatory follicle can be recognized as the largest (>10 mm diameter) healthy
follicle in either ovary. Because its granulosa cells express LH receptors coupled to aromat­
ase, this follicle continues to grow and secrete estradiol in the face of declining levels of
FSH. Basal levels of LH are sufficient to sustain preovulatory follicular growth and estrogen
secretion. Development-related paracrine signaling sustains the dominance of this follicle,
amplifying its responsiveness to FSH and LH. Modified from Hillier (1990).
increasingly responsive to LH (Figure 2). The individual contributions of
FSH and LH to this process are described in the following paragraphs.
C. Function of FSH
The primary signal for starting preovulatory follicular development is
increased secretion of FSH by the pituitary gland. This occurs in response
to the withdrawal of estrogen-mediated inhibition of pituitary FSH release
as the corpus luteum of the previous cycle regresses (Le Nestour et a\.,
1993). It takes 10-12 days of sustained stimulation by FSH for a ~5 mm
follicle to attain a full preovulatory diameter of >20 mm; during this time
the number of its granulosa cells doubles 5 or 6 times to reach over 50
million (McNatty, 1981). The FSH directly stimulates proliferation of granu­
losa cells and induces the LH-responsive mechanisms in these cells that
sustain steroid secretion by the preovulatory follicle and, after ovulation,
the corpus luteum (Richards et al., 1987).
Granulosa cells are the only cells in the female body known to possess
FSH receptors. When FSH is bound to its receptor on the cell surface,
adenylyl cyclase and cyclic adenosine monophosphate (cAMP)-dependent
protein kinase(s) are activated, leading to increased expression of the di-
4 Stephen G. Hillier
verse messenger ribonucleic acids (mRNAs) that encode the proteins cru­
cial to cytoproliferation and differentiation. The list of FSH-responsive
genes is extensive and at present includes aromatase (P450arom), the ste­
roidogenic cytochrome P450 crucial to estrogen synthesis (Hickey et al,
1988; Steinkampf et al, 1988); cholesterol side chain cleavage (P450scc),
which is rate-limiting in progesterone synthesis (Richards et al, 1987); the
LH receptor (Segaloff et al, 1990); several polypeptide growth factors and
their binding proteins, such as the insulin-like growth factors (IGFs) and
IGFBPs (Oliver et al, 1987; Voutilainen and Miller, 1987; Hernandez et al,
1992); proteolytic enzymes and inhibitors implicated in the mechanism of
follicular rupture at ovulation, such as tissue plasminogen activator (TPA)
(O'Connell et al, 1987) and plasminogen activator inhibitor (PAI) (Ny et al,
1985); local regulatory peptides such as inhibin, activin, and follistatin [see
160
6000
120
4000
80
2> 2000
3 40
3
ο
2>
Ε
α. •»-»
2, •πτη *- 0 D
Ο
10 100
Φc Ο
hFSH (ng/ml)
Ε
Έ
ο
Τ3
Φ 1
00
φ
hLH (ng/ml)
FIGURE 3 Dose-dependent effects of FSH (top) and LH (bottom) on thymidine uptake (open
circles) and estradiol production (closed circles) by human granulosa cells obtained from a
preovulatory follicle before onset of the LH surge. The cells were incubated for 4 days with
hFSH or hLH and 1.0 μΜ testosterone (aromatase substrate). Data are means ± SE. Repro­
duced with permission from Yong et al (1992b). Copyright © 1992 The Endocrine Society.