Proceedings of the 1982 Laurentian Hormone Conference

641 Pages·1983·14.708 MB·English

by  Roy O. Greep (Eds.)

RECENT PROGRESS IN
HORMONE RESEARCH
Proceedings of the
1982 Laurentian Hormone Conference
Edited by
ROY O. GREEP
VOLUME 39
PROGRAM COMMITTEE
G. D. Aurbach E. E. McGarry
J. D. Baxter A. Means
J. C. Beck B. W. O'Malley
H. Friesen J. E. Rail
R. O. Greep K. Savard
I. A. Kourides N. B. Schwartz
J. L. Vaitukaitis
1983
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LIST OF CONTRIBUTORS AND DISCUSSANTS
S. G. Amara T. Kono
G. D. Aurbach G. Koob
K. L. Barker I. A. Kourides
A-L. Barofsky J. Larner
F. C. Bartter C. Lazier
J. D. Baxter F. Lee
J. C. Beck R. Levine
L. Bilezikjian D. M. Linkie
N. C. Birnberg B. Little
F. Bloom B. A. Littlefield
P. Boyd-Leinen G. Martin Dani
M. R. Brown J-J. Mermod
C. P. Channing B. S. Milin
B. Chatterjee F. Morel
L. W. K. Chung N. M. Motwani
S. L. Cohen W. Moyle
D. V. Cohn G. H. Murdoch
W. F. Crowley T. S. Nath
G. R. Cunha M. I. New
G. B. Cutler C. S. Nicoll
W. F. Demyan M. B. Nikitovitch-Winer
D. E. Dobson R. Osathanondh
B. M. Dobyns H. Papkoff
P. K. Donahoe G. Pavlakis
R. A. Edgren E. J. Peck
J. Elting J. C. Penhos
R. M. Evans D. W. Pfaff
L. L. Ewing S. Ply mate
H. Fujii J. E. Rail
J. D. Gardner B. F. Rice
J. R. Gill G. Ringold
A. L. Goodman C. Rivier
R. O. Greep J. Rivier
J. R. Grove P. Robel
C. V. Hall M. G. Rosenfeld
D. H. Hamer A. K. Roy
G. D. Hodgen M. Saffran
R. A. Huseby M. J. Schiop
J. M. Hutson N. B. Schwartz
L. S. Jacobs R. Seelke
R. T. Jensen A. Segaloff
R. Jewelewicz J. M. Shannon
V. C. Jordan H. Shima
A. D. Kenny L. Sokoloff
O. L. Kon T. Spelsberg
vu
vin LIST OF CONTRIBUTORS AND DISCUSSANTS
J. Spiess J. Vaitukaitis
K. Sterling W. Vale
L. Swanson J. L. Vannice
O. Taguchi B. Zirkin
C. Thrall U. Zor
H. Toyoda
PREFACE
As this the thirty-ninth volume of Recent Progress in Hormone Re-
search, representing the proceedings of the 1982 Laurentian Hormone
Conference, goes to press it seems not amiss, perhaps even edifying, to
take a backward glance. The forerunner of this Conference, the Hormone
Conference of the American Association for the Advancement of Sci-
ence, met for the first time in 1943 at Gibson Island. There an unantici-
pated segregation problem arose. In 1944, through the kindly intercession
of the Montreal Physiological Society, the Conference met at Mt.
Tremblant Lodge in the Laurentian Mountains some ninety miles north-
west of Montreal. This setting for both formal and informal scientific
exchange proved to be propitious. At a return meeting in 1945 it was
unanimously voted to call the assembly the Laurentian Hormone Confer-
ence and to publish the papers and discussions.
In inaugurating this series of annual publications the editor, Gregory
Pincus, expressed the hope that "the publication of critical evaluations
and work-in-progress by leading authorities will be valuable not only as
records of knowledge and accomplishment but as excitements to re-
search. The spirit of inquiry dies without criticism and discussion, and it
is largely the purpose of these Conferences to nourish that spirit." What
was then a hope became an enduring reality from which there has been no
deviation. As with Volume 1, this volume will attest that in the field of
hormone research the spirit of inquiry remains very much alive and that
the Laurentian Hormone Conference from which this series derives re-
mains, as in Olympia, a gathering where the best is put to test. It has been
my good fortune to attend all but four of these Conferences, including the
one at Gibson Island, and to edit the last ten volumes of this series. On the
basis of that perspective it is clear that hormone research has been keep-
ing pace with the momentous advances in science and technology and
continues to offer challenging problems of great intrigue and biomédical
importance. To my knowledge the record of progress in hormone re-
search as depicted in these volumes remains unmatched elsewhere. Vol-
ume 39 is in keeping with that proud tradition.
Publication of the hour-long discussions following each paper is a
valuable feature of Recent Progress in Hormone Research. Persons chair-
ing these discussion sessions are carefully chosen for their relevant exper-
tise and nimbleness in the arena of issues and answers. For their services
in this capacity we are indebted to Drs. Ernest J. Peck, Alexander D.
Kenny, Murray Saffran, Gerald D. Aurbach, John D. Baxter, Iones
Kourides, Joseph Larner, and Maria New.
IX
X PREFACE
It is again my pleasure to thank our executive secretary, Martha
Wright, for efficient and dedicated attention to every aspect of the ar-
rangements for the 1982 Conference and the assemblage of all the copy for
this volume. To Lucy Felicissimo and Linda Carsagnini we extend our
gratitude for transcribing the tapes with skill and alacrity, and, as always,
the expertise and care lavished on the production of this volume by Aca-
demic Press is deeply appreciated.
Roy O. Greep
RECENT PROGRESS IN HORMONE RESEARCH, VOL. 39
The Ovarian Triad of the Primate Menstrual Cycle1
ARNOLD L. GOODMAN AND GARY D. HODGEN
Department of Physiology and Biophysics, University of Alabama in Birmingham,
Birmingham, Alabama, and Pregnancy Research Branch, National Institute of Child
Health and Human Development National Institutes of Health, Bethesda, Maryland
I. Introduction
To be offered so coveted a forum to present our findings on the work-
ings of the primate ovary leaves us flattered by the opportunity and awed
by the prospect of addressing such a distinguished audience. This good
moment derives much from the contributions of co-workers—the ener-
getic efforts of a cohort of imaginative postdoctoral fellows and the unre-
lenting labors of a talented and devoted technical staff. Speaking for all of
them, we are pleased that our efforts will become a part of the legacy of
The Gregory Pincus Memorial Lectures.
While not a strict chronicle, this presentation will review our efforts
aimed toward an improved understanding of the primate ovarian cycle
and the regulation of its endocrine and gametogenic activities, based on
studies in rhesus and cynomolgus monkeys. We will concentrate on a few
fundamental, unifying issues. These studies, along with the findings of
others, have enabled us to decipher and construct a clearer image of the
workings of the primate ovary. However, as you will see, what emerges is
far from a portrait in vivid color; rather, it is more a sketch in chiaroscuro.
II. The Ovarian Triad
As we began our work in the early 1970s, we were fortunate to have a
rather firm foundation on which to design our own studies on the regula-
tion of follicle growth. In particular, we had the advantage of drawing on
knowledge of the rhesus monkey menstrual cycle, provided by the classi-
cal studies of Hartman, Hisaw, Corner, Allen, van Wagenen, and Knobil,
among many others. Detailed characterizations of the human cycle by
Ross, Gemzell, Vande Wiele, Lunenfeld, Yen and others were also highly
1 The Gregory Pincus Memorial Lecture.
1
Copyright © 1983 by Academic Press, Inc.
All rights of reproduction in any form reserved.
ISBN 0-12-571139-5
2 ARNOLD L. GOODMAN AND GARY D. HODGEN
instructive. Without their solid contributions, our opportunities would
have been more constrained and our attempts less focused.
Since the fundamental themes of folliculogenesis appear to transcend
species differences, we considered them then, and again here, as axio-
matic for primates, as well. Unlike adult male mammals, which continu-
ously produce new sperm, female mammals are born with their lifetime
supply of eggs, enclosed in primordial follicles. This pool of primordial
follicles serves as a nonreplenished, progressively depleted stockpile (or
genetic bank) from which growing follicles (and oocytes) are continuously
withdrawn. As an adult, each mammalian female ovulâtes a species-char-
acteristic number of ova (the ovulatory quota) each week, month, season,
or year—the frequency again being a species characteristic. Thus, litter
size and annual fecundity rate of a species are proximately determined by
the physiology of the female through the size of the ovulatory quota,
frequency of the ovarian cycle, and the duration of pregnancy and lacta-
tion. The process of folliculogenesis may be seen as providing three prod-
ucts essential for successful reproduction: (1) the surge of estradiol secre-
tion to trigger the release of the preovulatory LH surge, (2) the
species-characteristic number of fertilizable haploid ova, and (3) the luteal
body(ies) and secretion of progesterone necessary to prepare the uterus
for implantation and to maintain at least the early stages of pregnancy.
Thus, this ovarian triad—the ovulatory follicle, oocyte, and corpus lu-
teum—must each function properly for successful reproduction; impair-
ment of follicle growth and secretion, oocyte maturation, or luteal func-
tion will preclude natural fertility.
III. Regulation of Folliculogenesis
A. SOME QUESTIONS
At first, the questions we posed were not new; indeed, they were much
the same as asked by earlier workers (Hisaw, 1947; Young, 1961). Later,
as our understanding improved, we began to ask more precise questions.
Some we have answered; others, including many important ones, remain
unanswered.
We accept as dogma that typically ovulation of a single, fertilizable
ovum each menstrual cycle completes a course of oogenesis that began
during fetal development. But, how is it that, from among the thousands
of follicles present from birth, only a relative few are recruited each cycle
to grow, at the same time others remain at rest? How is it that, from the
host of follicles maturing in each ovary, (typically) only a single follicle
THE OVARIAN TRIAD 3
escapes atresia and is selected to ovulate each cycle? Since the vast
majority of follicles falls victim to atresia (>99%), we recognized that
understanding the selection of the follicle destined to ovulate is fraught
with the inherent difficulty of studying the rare exception rather than the
predominant rule. As a consequence, we have tried to be assiduous in
distinguishing follicle growth that culminates in ovulation (gametogenic
follicle growth) from that ending in atresia (see illustrated overview of the
life cycle of the primate ovary—Fig. la and b).
The latter stages of oogenesis in adults (i.e., folliculogenesis) are known
to depend, to a large degree, on a complex interplay of hormones from the
hypothalamus, pituitary, and ovary. However, even though much more is
understood today of these endocrine relationships (diZerega and
ATRETIC GROWING OVULATED
FOLLICLES FOLLICLES FOLLICLES
PRE PUBERTAL FERTILE ADULT POST MENOPAUSAL
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BIRTH MENARCHE MENOPAUS
FIG. 1. (a) Pie chart depicting the fate of follicles as a function of age and as fraction of
the total present from birth, (b) Hypothetical curve depicting progressive depletion of viable
follicles from the ovary from fetal-life through menopause.
4 ARNOLD L. GOODMAN AND GARY D. HODGEN
Hodgen, 1981a; Knobil, 1980; Richards, 1979; Jones, 1978), what deter-
mines the fate of an individual follicle remains largely unknown. Is it
primarily extraovarian factors that regulate follicle growth, or do in-
traovarian factors play important governing roles, as well (Franchimont
and Channing, 1981; Jagiello and Vogel, 1981)? When is the follicle des-
tined to ovulate selected? Is it only events in the current cycle that deter-
mine the outcome, or do events in the preceding cycle(s) also influence
this process.
This last question leads immediately to another intriguing aspect of
folliculogenesis in monotocous primates, including women and maca-
ques: how just a single follicle matures to ovulation on only one ovary
each cycle, even though both ovaries are perfused by a common systemic
circulation. Since in higher primates both ovaries are functional (i.e., one
has not remained rudimentary), the maturation of a single follicle with the
potential to ovulate brings with it the obvious concomitant of one active
and one quiescent ovary each cycle. Is this ovarian asymmetry and side-
to-side partition of ovulation between cycles regulated or random? Do the
ovaries communicate, and, if so, how? Which comes first, so to speak, the
follicle or the ovary? That is, is one ovary in a given cycle somehow more
suited than the other to sponsor follicle development (as a consequence of
events in the preceding cycle?), or is ovarian asymmetry merely a conse-
quence of follicle selection?
B. A NASCENT HYPOTHESIS
As we attempt to answer some of these questions, we will also present
evidence in support of an emerging hypothesis of the regulation of follicle
growth and selection during the primate ovarian cycle. This hypothesis
suggests that many remaining answers, and doubtless new questions as
well, will be found within the ovary.
We hypothesize (1) that the precise regulation of follicle growth and
selection is accomplished primarily by specific ovarian factors that act
directly on the ovaries, and (2) that gonadotropins, at tonic levels, are
merely permissive to folliculogenesis. We envisage a two-tier ovarian
mechanism (Fig. 2). At the first tier, specific ovarian factors govern the
progressive winnowing of the cohort of developing follicles down to the
size of the species characteristic ovulatory quota each cycle. Some fac-
tors may act within the ovary of origin as intraovarian regulators; other
ovarian factors may be secreted and circulate to the opposite ovary, to act
as extraovarian signals (but of ovarian origin). Together, they regulate the
culling-out or inhibit the maturation of supernumerary growing follicles.
This first tier of the proposed ovarian mechanism, which precisely regu-