Table Of ContentSTEROID CONTRACEPTIVES
AND WOMEN'S RESPONSE
Regional Variability in Side-Effects
and Pharmacokinetics
REPRODUCTIVE BIOLOGY
J.
Series Editor: Sheldon Segal
The Population Council
New York. New York
Current Volumes in this Series
AIDS AND WOMEN'S REPRODUCTIVE HEALTH
Edited by Lincoln C. Chen. jaime Sepulveda Amor. and Sheldon j. Segal
AUTOCRINE AND PARACRINE MECHANISMS IN
REPRODUCTIVE ENDOCRINOLOGY
Edited by Lewis C. Krey. Bela j. Gulyas, and john A. McCracken
CONTRACEPTIVE STEROIDS: Pharmacology and Safety
Edited by A. T. Gregoire and Richard P. Blye
DEMOGRAPHIC AND PROGRAMMATIC CONSEQUENCES
OF CONTRACEPTIVE INNOVATIONS
Edited by Sheldon j. Segal. Amy O. Tsui. and Susan M. Rogers
ENDOCRINE AND BIOCHEMICAL DEVELOPMENT OF
THE FETUS AND NEONATE
Edited by jose M. Cuezva, Ana M. Pascual-Leone, and Mulchand S. Patel
GENETIC MARKERS OF SEX DIFFERENTIATION
Edited by Florence P. Haseltine, Michael E. McClure, and Ellen H. Goldberg
REPRODUCTIVE TRACT INFECTIONS: Global Impact and Priorities for
Women's Reproductive Health
Edited by Adrienne Germain, King K. Holmes. Peter Piot. and judith Wasserheit
STEROID CONTRACEPTIVES AND WOMEN'S RESPONSE: Regional
Variability in Side-Effects and Pharmacokinetics
Edited by Rachel Snow and Peter Hall
UTERINE AND EMBRYONIC FACTORS IN EARLY PREGNANCY
Edited by jerome F. Strauss III and C. Richard Lyttle
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STEROID CONTRACEPTIVES
AND WOMEN'S RESPONSE
Regional Variability in Side-Effects
and Pharmacokinetics
Edited by
Rachel Snow
Harvard School of Public Health
Boston, Massachusetts
and
Peter Hall
World Health Organization
Geneva, Switzerland
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging-in-Publication Data
Steroid contraceptives and women's response: regional variability in
side-effects and pharmacokinetics I edited by Rachel Snow and Peter
Ha II,
p. cm. -- (Reproductive biology)
"Proceedings based on a Symposium on Steroid Contraceptives and
Women's Response: Regional Variability in Side-Effects and Steroid
Pharmacokinetics, held October 21-25, 1990, in Exeter, New
Hampshire"--T.p, verso.
Includes bibl iographical references and index.
ISBN 0-306-44718-5
1, Oral contraceptives--Side effects--Congresses. 2. Oral
contraceptives--Pharmacokinetics--Congresses. 3. Women--Physlology
-Congresses. 4. Steroid hormones--Derlvatives--Congresses.
I. Snow, Rachel. II. Hall, Peter, 1943- III. Symposium on
Steroid Contraceptives and Women's Response: Regional Variability in
Side-Effects and Steroid Pharmacokinetics (1990 : Exeter, N.H.)
IV. Series.
[DNLM: 1. Contraceptive Agents, Female--adverse effects
-congresses. 2. Contraceptive Agents, Female--pharmacokinetics-
-congresses. 3, Steroids--pharmacoklnetics--congresses. QV 177
S839 1994]
RG137.5,S756 1994
615' . 766--d c20
DNLM/DLC
for Library of Congress 94-21617
CIP
Proceedings based on a Symposium on Steroid Contraceptives and Women's Response:
Regional Variability in Side-Effects and Steroid Pharmacokinetics,
held October 21-25, 1990, in Exeter, New Hampshire
ISBN 0-306-44718-5
©1994 Plenum Press, New York
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y, 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by
any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written
permission from the Publisher
PREFACE
Pharmacokinetic variability of contraceptive steroids is a relatively under-explored
area of contraceptive research, and hardly a common point of discussion among those who
plan and deliver family planning services. Nevertheless, numerous independent studies over
the last 15 years have indicated that women in different regions of the world vary in their
pharmacokinetic response to contraceptive steroids. The causes of such variability are not
known, but it has important consequences for contraceptive effectiveness. It may also offer
insight to the basis of contraceptive side-effects.
The impetus for this volume was to collect documentation of pharmacokinetic
variability of contraceptive steroids, and to explore both the possible causes and implications
of these data. Factors known to affect steroid pharmacokinetics, such as concurrent use of
specific medications, are reviewed by Back and Orme. Other factors known to affect
endogenous steroid dynamics are presented in chapters by Bradlow, Longcope, Goldin and
Snow, because of their possible role in contraceptive steroid pharmacokinetics.
Regarding the clinical consequences of pharmacokinetic variability, different blood
levels of depo medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET
EN) among Mexican and Thai women have been associated with differences in contracep
tive effectiveness; likewise, blood concentrations of levonorgestrel (LNG) among NorplantR
users are associated with effectiveness of the method. Regrettably, there is little other data
regarding the implications of pharmacokinetic variability. For example, we do not know
whether variability in blood concentrations of the magnitude observed in these studies are
associated with differences in physiologic parameters (such as endometrial affects) or with
other side-effects. To date, studies on pharmacokinetic variability have rarely monitored
contraceptive side-effects as pharmacodynamic parameters.
This volume also includes several papers addressing the prevalence of contraceptive
side-effects, and more general questions regarding clinet satisfaction with steroid contracep
tives. We have included such papers in this volume to underscore our interest in seeing
vi Preface
greater attention given to possible associatlions between phannacokinetic parameters and
women's experience of contraceptive side-effects.
As the 1994 Cairo World Population Congress approaches, there is increasing clamor
for birth control scientists to integrate their research objectives with efforts to promote
women's reproductive health and social well-being. In that regard, this book is timely, as
it underscores a defined area of research that would explore the physiologic synergies
between women's metabolic response to contraception and their response to such
technologies. The multi-disciplinary authorship of this volume also models the kind of
scientific-programmatic dialogue that is required for doing meaningful research and bringing
the fruits of such research to bear on program delivery.
This volume represents a collaborative effort between Harvard University, the Special
Programme for Research, Development and Research Training in Human Reproduction
(HRP) at the World Health Organization, and the International Planned Parenthood
Federation (IPPF), and we are grateful to the support of Mahmoud Fathalla and Halfdan
Mahler for this effort. We are also grateful to Sheldon Segal for his advice and support at
several critical junctures in the evolution of this volume.
We also wish to thank Vanessa Bingham, Wayne Chueng, Sarah Hemphill, and Jean
Joseph for their technical assistance during the editorial process, and most especially Pat
Vann and the staff at Plenum Press for their patient and meticulous production of this book.
Finally, we are grateful to acknowledge support by the Ford Foundation for a
meeting on Steroid Contraceptives and Women's Response: Regional Variability in Side
Effects and Steroid Pharmacokinetics, which took place in Exeter New Hampshire in
October of 1990, and where many of the chapters were originally presented. Our extended
thanks to Jose Barzelatlo and others at the Ford Foundation for their interest in this project.
Rachel Snow
October 1993
CONTENTS
Why Pharmacokinetics? An Introduction and Overview
Rachel C. Snow and Lucy E. Wilson . . . . . . . . . . . . . . . . . . . . . . . . . ..... .
EXPERIENCE WITH CONTRACEPTIVE SIDE EFFECTS
Selection of a Contraceptive: What Guides a Woman?
Pramilla Senanayake .......................................... 9
Contraceptives and Women's Complaints: Preliminary Results from the Post-Marketing
Surveillance of Norplant®
Yasmin Ahmed, S. Boccard, T. Farley, O. Meirik ..................... 15
Regional and Individual Variation in Bleeding Patterns Associated With
Steroid Contraception
Elizabeth M. Belsey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 27
Variability in Menstrual Bleeding Patterns: Comparing Treated and Untreated
Menstrual Cycles
Sioban D. Harlow ................ . . . . . . . . . . . . . . . . . . . . . . . . . .. 55
Contraceptive Use and Discontinuation: The Social Meaning of Side-Effects
Carla Makhlouf Obermeyer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 61
VARIABILITY IN STEROID PHARMACOKINETICS
Population and Delivery Systems: Variability in the Pharmacokinetics of Long-Acting
Injectable Contraceptives
Josue Garza-Flores, Sang Guo-Wei and Peter E. Hall. . . . . . . . . . . . . . . . . .. 69
Pharmacology of Ethynl Estrogens in Various Countries
Joseph W. Goldzeiher ......................................... 85
Pharmacokinetics of Norplant® Implants
Harold A. Nash and Dale N. Robertson ............................. 91
vii
viii Contents
Pharmacokinetic Drug Interactions with Oral Contraceptives
David J. Back and M.L'E. Orme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 103
A Critical Evaluation of the Pharmacokinetics of Contraceptive Steroids
Kenneth F otherby ........................................... 125
A Short Review on the Sources of Variability in Pharmacokinetic Parameters of Sex
Steroids: Comment on the Paper by K. Fotherby
Michael Hiimpel ............................................ 133
LESSONS FROM ENDOGENOUS METABOLISM
Diet and Estrogen Metabolism
Christopher Longcope ........................................ 143
Diet, Circulating Estrogen Levels and Estrogen Excretion
Barry R. Goldin ............................................ 153
Variations in Estrogen Metabolism: Commentary on B. Goldin
Leon Bradlow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 171
Body Fat, Fat Topography and Endogenous Steroid Metabolism
Rachel Snow .............................................. 179
IMPLICATIONS FOR POLICY AND PROGRAMS
Steroid Contraceptives and Women's Response: Program Considerations from the
Quality of Care Perspective
Joan Kaufman. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 187
Bringing a Client and Life-Cycle Perspective to Scientific Evidence
Judith Bruce . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 199
Commentary on Presentation of Dr. Pramilla Senanayake
Gary S. Grubb ............................................. 207
A Clinician's Perspective
Soledad Diaz .............................................. 213
FUTURE RESEARCH DIRECTIONS
Regional Population Differences and Population Pharmacokinetics of Steroidal
Contraceptives
Sang Guo-Wei ............................................. 219
Variability in Steroid Pharmacokinetics: Needs for Future Research
Laneta J. Dorflinger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 239
Contents ix
Experimental Design for Future Research
James Trussell ............................................. 247
Looking Forward: New Research Priorities
Lincoln Chen .............................................. 251
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 257
Index ...................................................... 261
WHY PHARMACOKINETICS? AN INTRODUCTION AND OVERVIEW
Rachel C. Snow, and Lucy E. Wilson 1
In the last two decades, worldwide contraceptive use has risen dramatically, and
much of this increase took place in the developing world. From 1960-65 to 1990 the
percentage of couples using contraceptives in developing countries rose from 9 to almost
51 percent (United Nations Population Fund 1991). This increase reflects the adoption of
three principle types of contraceptives: sterilization, intra-uterine devices, and hormonal
methods. Of the approximately 400 million persons contracepting in the late 1980's, 155
million were sterilized, 61 million used hormonal methods and 80 million used the IUD.
Different methods appear to be favored (either by providers or clients) in different regions.
The global popularity of sterilization and the IUD reflects the popular use of these methods
in Asia and the Pacific, the region where 64% of the 400 million contraceptors are living.
Yet hormonal methods account for 31 % of total use in the Americas and they account for
50% of all method use in Africa (Mauldin and Segal 1988). A recent report on contra
ceptive use in Sub-Saharan Africa (SSA) suggests that as countries shift from low
contraceptive prevalence to higher levels, traditional methods give way to hormonal
contraception, followed by a rapid adoption of female sterilization (National Research
Council 1993).
Steroid methods of contraception offer numerous features to recommend them, and
they are likely to remain a significant offering of family planning services for many years
to come. They are highly effective, they incur few, if any, medical risks for healthy
women, they are available with different modes of administration, some with a range of
dosages, and they generally require low maintenance by the user.
The problem of side-effects
But steroids contraceptives, for all their benefits, are blunt instruments, and many
women experience side effects with steroid contraception that are prohibitive, or at best,
discouraging. Among contraceptive users in Thailand, reports of side effects are highest
among women using injectable steroids (almost 41 percent) and oral contraceptives (38
percent) (Stephen and Chamratrithirong 1988). Among women surveyed in eight
developing countries (Grubb 1987), from 26 to 80 percent of users had stopped taking oral
1 R. Snow, L. Wilson • Department of Population and International Health, Harvard School of Public
Health, 665 Huntington Avenue, Boston, MA 02115.
Steroid Contraceptives and Women's Response,
Edited by R. Snow and P. Hall, Plenum Press, New York. 1994
