Clinical guide for contraception (5th edition)

years, fewer teens have received instruction regarding contraception.11 Th e evidence overwhelmingly indicates that abstinence programs have not had a positive impact on teen sexual beha

A CLINICAL GUIDE FOR

Professor of Obstetrics, Gynecology and Reproductive Sciences

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10 9 8 7 6 5 4 3 2 1

This Fifth Edition is published 50 years after the introduction of the birth

control pill to American women and their clinicians We dedicate this book to

the creative, courageous, and generous women and men who worked together

to develop the first modern method of contraception The pill brought women,

including our seven daughters, new freedom, equality, and opportunity We

hope that the next 50 years will see an ever wider choice of contraceptives help

all the world’s women to lead healthier, happier lives.

Preface vii

Contraception in the United States 1

Oral Contraception 19

Special Uses of Oral Contraception 153

Emergency Contraception • The Progestin-Only Minipill Vaginal and Transdermal Estrogen-Progestin Contraception 167

Implant Contraception 183

Injectable Contraception 217

Intrauterine Contraception 239

Barrier Methods of Contraception 281

Natural Family Planning: Periodic Abstinence and Withdrawal 315

The Postpartum Period, Breastfeeding, and Contraception 327

Clinical Guidelines for Contraception at Different Ages: Early and Late 351

Sterilization 381

Induced Abortion and Postabortion Contraception 405

Interpreting Epidemiologic Reports and Contraceptive Eligibility Criteria 429

Epilogue 439 Index 441

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Contraception, socially recognized and accepted only in the last 50 years,

is both an essential and a complicated part of modern life ception has separated sex from procreation and has provided couples greater control and enjoyment of their lives It is a critical element in limiting population, thus preserving our planet’s resources and maintaining quality of life for ourselves and our children Contraception is both a personal and a so-cial responsibility

Contra-Th e above accomplishments could not be achieved by the simple ceptive methods employed before the late 20th century Greater eff ectiveness and ease of use required more complicated methods, associated with greater consequences to our health Intensive study of these issues has yielded an enormous wealth of information, making an informed choice possible but not easy

contra-In this book, we have distilled and formulated the information essential for the intelligent use of contraception Th e current state of knowledge and variety of contraceptive options allow clinicians and patients to select meth-ods best suited to an individual’s personal, social, and medical characteristics and requirements But even now, science is still sometimes inadequate, and medical judgments must be made without the comfort of scientifi c support

In these situations, we have expressed our opinion, refl ecting our knowledge and our clinical experience

We hope our text will help all health care professionals who have assumed the social responsibility of assisting couples to use safe, eff ective contraception

1 Contraception in the United States

Fertility decreases as societies become more affluent This decrease is a

response to the use of contraception and abortion During her ductive lifespan, the average !Kung woman, a member of an African tribe of hunter-gatherers, experienced 15 years of lactational amenorrhea,

repro-4 years of pregnancy, and only repro-48 menstrual cycles.1 In contrast, a modern urban woman will experience 420 menstrual cycles Contemporary women undergo earlier menarche and start having sexual intercourse earlier in their lives than in the past Even though breastfeeding has increased in recent years, its duration is relatively brief and its contribution to contraception in the developed world is trivial Therefore, it is more difficult today to limit the size of a family unless some method of contraception is utilized

Today, more women younger than age 25 in the United States become pregnant than do their contemporaries in other Western countries.2–4 Th e U.S teenage pregnancy rates are twice as high as those in England, Wales, and Canada and eight times as high as those of the Netherlands and Japan.5

Th e diff erences disappear almost completely aft er age 25 Th is is largely because American men and women aft er age 25 utilize surgical sterilization

at a high rate

It is not true that young American women want to have these higher pregnancy rates About 82% of all pregnancies among American teenagers are unintended.6 Increasing eff ective contraceptive use among young Amer-icans began to have an impact in 1991 In the 1990s, the teenage pregnancy rate reached the lowest rate since estimates began in 1976, a 21% decline from 1991 to 1997 for teenagers 15 to 17 years and a 13% decline for older teenagers.7 Overall, there was a 17% decline in teenage birth rates and a 12.8% decline in teenage-induced abortions from 1991 through 1999 From

1995 to 2002, 14% of the decline in teen pregnancy was a consequence of decreased sexual activity among U.S teenagers; however, 86% of the decline was attributed to an increase in the use of eff ective contraception.8 In 2004, the proportion of induced abortions in the United States obtained by teens reached a low of 17%.9

Aft er a 14-year 34% decline, birth rates for teenagers began to increase in

2005, the fi rst increase since 1991 Th e rate increased 5% between 2005 and

2008.10 Th ere is appropriate concern that this increase refl ects diffi culties

in contraceptive access, aff ordability, and correct use In addition, in recent

years, fewer teens have received instruction regarding contraception.11 Th e

evidence overwhelmingly indicates that abstinence programs have not had

a positive impact on teen sexual behavior, including the delay of the

initia-tion of sex or the number of sexual partners.12 In contrast, comprehensive

sex education programs that include contraception are eff ective and do not

increase the frequency of sex or hasten the initiation.13

Nearly half of all pregnancies (49%) in the United States are unplanned, and about 40% of these are aborted.6,14 American teenagers abort about 34%

of their pregnancies, and this proportion is similar to that seen in other

countries.5 But older American women, aged 20 to 34, have the highest

pro-portion of pregnancies aborted compared with other countries, indicating

that an unappreciated, but real, problem of unintended pregnancy still exists

beyond the teenage years In fact, American women older than age 40 have

had for the last 2 decades a high ratio of abortions per live births, a ratio very

similar to that of teenagers.9

Delaying marriage prolongs the period in which women are exposed to the risk of unintended pregnancy Th is, however, cannot be documented

as a major reason for the large diff erential between young adults in Europe

and the United States Th e available evidence also indicates that a diff

er-ence in sexual activity is not an important explanation Th e major diff erence

between American women and European women is that American women

under age 25 are less likely to use any form of contraception Signifi cantly,

the use of oral contraceptives (the main choice of younger women) is lower

in the United States than in other countries

Why are Americans diff erent? Th e cultures in areas such as the United Kingdom and the Scandinavian countries are certainly very similar with sim-

ilar rates of sexual experience A major diff erence must be attributed to the

availability of contraception In the rest of the world, contraceptive services

can be obtained from more accessible resources and relatively inexpensively

Major American problems are the enormous diversity of people and the

unequal distribution of income in the United States Th ese factors infl uence

the ability of our society to eff ectively provide education regarding sex and

contraception and to eff ectively make contraception services available

In 1966, a report from NASA placed our technological achievements into historical perspective.15 Eight hundred lifespans can bridge more than

50,000 years But of those 800 people

650 spent their lives in caves,

developed within the lifespan of the 800th person

Th e era of modern contraception dates from 1960 when intrauterine devices

(IUDs) were reintroduced and oral contraception was fi rst approved by the

U.S Food and Drug Administration For the fi rst time, contraception did not have to be a part of the act of coitus However, national family planning services and research were not funded by the U.S Congress until 1970, and the last U.S law prohibiting contraception was not reversed until 1973

Contraception is not new; but its widespread development and tion are new It is in the latest tick of the Earth’s time clock that safe control of fertility is now possible Th is book is dedicated to that end Th is chapter will present an overview of the effi cacy of contraceptive methods, a summary of con- traceptive use in the United States and the world, and a brief look at the future.

A clinician’s anecdotal experience with contraceptive methods is truly

insuf-fi cient to provide the accurate information necessary for patient counseling

Th e clinician must be aware of the defi nitions and measurements used in assessing contraceptive effi cacy and must draw on the talents of appropri-ate experts in this area to summarize the accurate and comparative failure rates for the various methods of contraception Th e publications by Trussell

et al.,16–20 summarized below, accomplish these purposes and are highly recommended

Defi nition and Measurement

Contraceptive effi cacy is generally assessed by measuring the number of unplanned pregnancies that occur during a specifi ed period of exposure to and use of a contraceptive method Th e two methods that have been used to measure contraceptive effi cacy are the Pearl index and life-table analysis

The Pearl Index

Th e Pearl index, created by Raymond Pearl in 1933, is defi ned as the number

of failures per 100 woman-years of exposure.21 Th e denominator is the total months or cycles of exposure from the onset of a method until completion

of the study, an unintended pregnancy, or discontinuation of the method

Th e quotient is multiplied by 1,200 if the denominator consists of months or

by 1,300 if the denominator consists of cycles

With most methods of contraception, failure rates decline with tion of use Th e Pearl index is usually based on a lengthy exposure (usually

1 year) and, therefore, fails to accurately compare methods at various tions of exposure Th is limitation is overcome by using the method of life-table analysis

dura-Life-Table Analysis

Life-table analysis calculates a failure rate for each month of use A lative failure rate can then compare methods for any specifi c length of exposure Women who leave a study for any reason other than unintended pregnancy are removed from the analysis, contributing their exposure until the time of the exit

Contraceptive Failures

eff ectiveness” and “use eff ectiveness” have been used to designate effi cacy

with correct and incorrect use of a method It is less confusing to simply

compare the very best performance (the lowest expected failure rate) with

the usual experience (typical failure rate) as noted in the table of failure rates

during the fi rst year of use Th e lowest expected failure rates are determined

in clinical trials, in which the combination of highly motivated subjects and

frequent support from the study personnel yields the best results

Contra-ceptive typical failure rates have been estimated using the data from the

1995 and 2002 U.S National Survey of Family Growth, correcting for the

underreporting of induced abortion.19,20,22

Th e 2002 estimates of failure were not signifi cantly diff erent compared with the previous estimates from the 1995 national survey Women over the

age of 30 were less likely to experience failure than young women; teens were

more than twice as likely to experience a failure than older women Hispanic

women and even more so, black women, experienced higher failure rates

Groups that were less likely to experience contraceptive failure were women

who did not intend to have a subsequent birth and women who had no

previous births Married women experienced the lowest failure rates and

cohabiting women the highest Th e most important determinants of pill

fail-ure, therefore, were age, intention toward a future birth, parity, and marital

status Interestingly, once these factors were accounted for, duration of use,

race, ethnicity, and poverty status no longer aff ected the risk of pill failure

Th e same factors infl uence condom use, but when corrected for these

fac-tors, race, ethnicity, and poverty aff ected the risk of condom failure

Th is is a subject of great interest because the rate of unintended cies in the United States continues to be high About one half (over 3 million)

pregnan-of all pregnancies in the United States are unintended, and in 2002, about

53% of those occurred in women using a method of contraception.6,14,23 Here

is a more striking statistic: one of every two American women aged 15 to 44

has experienced an unintended pregnancy.14

Method

Percent of Women with Pregnancy

(Continued)

Method

Percent of Women with Pregnancy

Contraceptive Use in the United States

Th e National Survey of Family Growth is conducted by the National Center

for Health Statistics of the Centers for Disease Control and Prevention Data

are available from 1972, 1976, 1982, 1988, 1995, and 2002.23–28 Th e samples

are very large; therefore, the estimates are very accurate

Pregnancy rates in the 1990s declined for women younger than age

30 years and increased in older women From 1990 to 1997, the decrease in

women in their early 20s was 8%, and the increase in women in their early

30s was 3% Th e percent of married couples using sterilization as a method

of contraception more than doubled from 1972 to 1988 and has remained

stable since then Th e use of oral contraception reached a high in 1992,

slightly decreased in 1995, especially among Hispanic and black

Ameri-cans, and returned to 31% of contracepting women in 2002 Approximately

10.7 million American women used oral contraceptives in 1988 and

11.6 million in 2002 Among never married women and women under

age 25, oral contraception is the leading method of birth control About 53%

of contracepting women under age 25 were using oral contraception in 2002

From 1988 to 2002, oral contraception rose to 32% among women aged 30 to

44 of contraceptors aged 30 to 34 and 11% among those aged 40 to 44 About

5.3% of contraceptors in 2002 were using the 3-month injectable method

and 1.2% transdermal, vaginal ring, and implant methods

In the 1990s, there was an increase in condom use by never married and formerly married women, women younger than 25, black women, and

Hispanic women Th ese changes refl ected the concern regarding sexually

transmitted infections (STIs), including human immunodefi ciency virus

But in 2002, the use of condoms alone returned to the level observed in the

1980s, probably because of the use of transdermal, vaginal ring, implant,

Percent

1973 1982 1988

9

23 27

8

11 12

25 28 31

7 7

2 0.8

Female sterilization Male sterilization Pill IUD

27 27

11 9.2

27 31

12

2 15

and injectable methods About one third of condom users in 2002 were using more than one method, especially younger and never married women, including use of an oral contraceptive and a condom in 14% at fi rst inter-course! Most importantly, the percentage of women who used a contracep-tive method at their fi rst premarital intercourse increased from 43% before

1980 to 79% in 2002 Condom use at fi rst intercourse increased from 22%

before 1980 to 67% in 2002

In 1982, 56% of U.S women, 15 to 44 years of age, were using ception, and this has increased to 62% (about 40 million women) In 2002, contraceptive sterilization (male and female) was utilized by 36% of these

num-ber of reproductive-aged women using the IUD decreased by two-thirds from 1982 to 1988 and further decreased in 1995, from 7.1% to 2% to 0.8%, respectively but rose to 2% in 2002 IUD use is concentrated in the United States in married women older than age 35 In 1982, more than 2 million women (about 8% of contraceptors) used the diaphragm, but use of the dia-phragm has nearly disappeared in the United States (0.3% of contracepting women in 2002)

Injectable

27 23 21

53 52

38

Pill

0 1 4

Male

4 15 27

Female

41

50 45

9 14 18

32 19 11

17 16 11

4 1.6

Condom

2

Contraceptive Use by Age in 2002 23,24

15–19 Years 20–24 Years 25–29 Years 30–34 Years 35–39 Years 40–44 Years

Contraceptively Surgically Sterile Nonsurgical Contraceptors

Th e oral contraceptive (53%) and condoms (27%) are the most popular methods among teenagers However, studies have repeatedly documented that the use of the implant and injectable methods is associated with lower discontinuation rates and a lower rate of repeat pregnancies following delivery.29,30 Th is warrants continuing eff orts to extend the use of these methods

In 2002, 62% of all women 15 to 44 years of age were using some method

of contraception, whereas 38% of women of reproductive age were not using

a method of contraception for the following reasons:

7.4% — At risk for an unintended pregnancy.

Th e women at risk for an unintended pregnancy increased by 1.43 million

women (2.2%) from 1995 to 2002, and the increase was in all age groups

Th ese women accounted for more than half of unintended pregnancies in

the United States; of the rest, about 43% are a consequence of incorrect

con-traceptive use; only 5% can be attributed to method failure.14,20 Th is increase

alone in women at risk and not using contraception, therefore, would amount

to about 500,000 unintended pregnancies and 270,000 induced abortions in

2002 In our view, these numbers refl ect problems of contraceptive access,

aff ordability, and correct use in the United States Th e number of unintended

pregnancies is highest among low-income women, women who have not

completed high school, women aged 18 to 24, unmarried, especially

cohab-iting, women, and members of racial or ethnic minority groups.6

U.S couples have made up for the lack of contraceptive eff ective use and availability by greater reliance on voluntary sterilization Between 1973 and

1982, oral contraception and sterilization changed places as the most

popu-lar contraceptive method among women over the age of 30 Approximately

one half of American couples choose sterilization within 15 to 20 years of

their last wanted birth During the years of maximal fertility, oral

of condoms is the second most widely used method of reversible

contra-ception, rising from about 9% in the mid-1980s to approximately 26% of

contracepting women in 1995, decreasing to 18% in 2002.23,24

Overall use of contraception among women at risk of unintended nancy decreased from 92.5% in 1995 to 89.3% in 2002.20 Th e use of con-

preg-traception among poor women at risk of pregnancy decreased from 92.1%

in 1995 to 86.3% in 2002 For various reasons, American women have had

increasing diffi culty in obtaining eff ective contraception

Women at each end of the economic spectrum, the poorest and the wealthiest, experienced a decrease in failure rates from 1995 to 2002,

although the poorest women continued to have a higher failure rate than

did the better-off women Also, although the diff erence in overall failure rate

was not statistically signifi cant comparing 1995 and 2002, there was about a

2.5% improvement; this missed mathematical signifi cance but it may refl ect

a meaningful change in our population Th is change is probably due to an

increase in pill and injectable methods and a decrease in condom use

dur-ing this period of time Women livdur-ing in poverty who must rely on condoms

or withdrawal (male-dependent methods) have about a 2-fold increase in

failure rates, but if they can use the pill, their failure rates are the same as

It is not enough to say the obvious—that we need greater education—

but we need to learn where and when education is most eff ective, where is money best spent, and how to maximize the choices available for all women

Th is is not a task just for professional health care providers; it is a widespread social problem that requires policy and budgeting decisions Th e problems

are more sociologic, such as cost and insurance coverage (and the

ridicu-lous insurance practice of providing pills only 1 month at a time) Th ese are reasons why other countries have lower percentages of women at risk for unintended pregnancies

Th e pattern of contraceptive use in Canada is similar to that of the United States, with a similar percentage of oral contraceptive use (about 43% of women

15 to 44 years of age) and a slightly lower use of sterilization.31,32 Canada, too, has seen an increase in condom use and a decrease in the use of the IUD

In England, the primary method of contraception is oral contraception (28%) followed by condoms (24%), the IUD (4%), and injectable methods (3%);

7% of the reproductive-aged women and 10% of the men have been ized.33 In France, 49% of reproductive-aged women use oral contraceptives, and although IUD use has slightly decreased (only among younger women), French women use the IUD at a rate that is more than 16-fold greater compared with North American women.34,35 Most French women use oral contraceptives when young and then turn to the IUD in their older years (only 4.1% of French women relied on sterilization; male sterilization is virtually nonexistent)

steril-Induced Abortion in the United States

Th e number of abortions performed in the United States has been ing since a peak was reached in 1981, totaling 1.33 million in 1993 and 1.18 million in 1997, with the greatest decline among teenagers.36–38 Th is is partly because the number of pregnancies in the United States has been decreasing and the proportion of reproductive-aged women younger than age 30 is also decreasing.39 Accounting for underreporting, a more accurate estimate indi-cated about 1.36 million induced abortions in 1996, 1.31 million in 2000, and 1.21 million in 2005, the lowest number since 1976.9,40–42 In 2004 and

decreas-2005, 57% of induced abortions were obtained by women in their 20s and

17% by women younger than 20 Th e number of births in the United States, including teenage births, began to increase in 2005,10,43 and it is anticipated

abortion numbers will parallel this recent change.

Overall, a little over 3 million (49%) of American pregnancies each year are unintended, but the percentage is only 40% among white women in con-

trast to 54% among Hispanics and 69% among blacks.6,9 Each year, 42% of

unintended pregnancies are terminated by induced abortions, and 60% of

these abortions are obtained by women who have one or more children Th e

rate of unintended pregnancies and abortions is about four times higher

among poor women

The Impact of the Worldwide Use of Contraception

Th e world population is expected to stabilize at above 10 billion aft er 2180,

with a fertility rate of 2.1 children per woman.44 Approximately 96% of the

population growth now occurs in developing countries so that by 2050, 10%

of the population will live in developed countries, a decrease from the

cur-rent 25% Today, the fertility rate is about 1.6 children per women in China,

Eastern and Western Europe, North America, Japan, Australia, and New

Zealand.44 Some time aft er 2020, all of the growth in global population will

occur in developing countries

Th roughout the world, 45% of married women of reproductive age tice contraception However, there is signifi cant variation from area to area;

prac-for example, more than 70% in the United States and China but only 6%

in Nigeria.45 About 71 million married women living in developing

coun-tries are at risk of an unplanned pregnancy.46 Less than 15% of women of

Population (in billions)

0.3

1000

0 2 4 6 8 10

Th e problem in the developing world is self-evident Th e ability to regulate fertility has a signifi cant impact on infant, child, and maternal mortality and morbidity A pregnant woman has a 200 times greater chance of dying if she lives in a developing country rather than in a developed country.47 Th e health risks associated with pregnancy and childbirth in the developing world are far, far greater than risks secondary to the use of modern contraception.48 To meet the projected growth in the world’s population, the number of women using family planning will need to increase substantially from 1998 to 2025;

for example, 40 million more women in India will need to use some method

of contraception!45 In the developing world, about 140 million women who

do not want to get pregnant are not using contraception

In recent years, there has been an appropriate shift from a narrow focus

on contraception to a broader view that encompasses the impact of erty, emphasizes overall well-being and the rights of individuals, endorses gender equality, and examines the interactions among these issues.49 It is not enough to simply limit fertility; contraception is only one component of reproductive health

pov-The Impact of Use and Nonuse

Inadequate access to contraception is associated with a high induced tion rate Eff ective contraceptive use largely, although not totally, replaces the resort to abortion Th e combination of restrictive abortion laws and the

lack of safe abortion services continues to make unsafe abortion a major

cause of morbidity and mortality throughout the world, especially in many

developing countries where abortion services are illegal.50 Both safe and

unsafe abortions can be minimized by maximizing contraceptive services

However, the need for safe abortion services will persist because

contracep-tive failures account for about half of the 1.2 million annual induced

abor-tions in the United States.51

In the United States, money spent on public funding for family planning saves money spent on medical, welfare, and nutritional services.52 States

with higher family planning expenditures have fewer induced abortions,

low–birth-weight newborns, and premature births.53 Th e investment in

family planning leads to short-term reductions in expenditures on maternal

and child health services and, aft er 5 years, a reduction in costs for

edu-cation budgets Cutting back on publicly funded family planning services

largely aff ects poor women, increasing the number of unintended births and

abortions

Sexually Transmitted Infections and Contraception

Th e interaction between clinician and patient for the purpose of

contracep-tion provides an opportunity to control STIs Th e modifi cation of unsafe

sexual practices reduces the risk of unplanned pregnancy and the risk of

infections of the reproductive tract A patient visit for contraception is an

excellent time for STI screening; if an infection is symptomatic, it should

be diagnosed and treated during the same visit in which contraception is

requested A positive history for STIs should trigger both screening for

asymptomatic infections and counseling for safer sexual practices

Atten-tion should be given to the contraceptive methods that have the greatest

infl uence on the risk of STIs

Global Warming and Contraception

In the midst of politics and philosophy heavily promoting a “green” eff ort

to limit global warming, a very important point is being ignored Even

small increases in population have a major impact on the global environment,

including excessive consumption of resources in affl uent societies.

political economist, published six editions of his famous book, An Essay

on the Principle of Population, between the years 1798 and 1826 Th e

Mal-thusian hypothesis can be expressed very simply: the human population

will outgrow the world’s resources needed for its support Malthus argued

that population could be controlled only by a high death rate or a low birth

rate But because he did not approve of birth control, he concluded that a

high death rate would be necessary, caused by misery, in the form of wars,

famine, and disease, and vice (contraception was in this category, along

with murder) Without misery and vice, overpopulation, therefore, would lead to poverty, an animalistic competition for food, and a general loss of civilization

Th e Malthusian hypothesis has been resurrected in recent times Th ere

is a growing awareness that our planet is running out of clean air, potable water, and specifi c agricultural and mineral commodities Optimists look to the power of technology and human creativity to solve this Malthusian prob-lem, but the acute need for eff ective contraception cannot be ignored, as it

is by most economists Eff ective family planning programs not only benefi t individuals but also national economies and the global environment Th e need and demand for family planning are extant in every part of our world, although greatest in the developing countries Lacking is the required politi-cal and fi nancial commitment An appreciation for the impact on global warming can provide added motivation

Contraception and Litigation

Clinicians are concerned about the prospect of bad outcomes associated with contraceptive use leading to litigation Multimillion dollar verdicts and settlements in favor of plaintiff s who have used products as innocent

as spermicides capture national attention Actually, these events are very unusual compared with the widespread use of contraception

Th e best way to avoid litigation is good patient communication Patients who sue usually claim there were contraindications or risks that were not conveyed by the clinician Th e best way to infl uence litigation is to keep good records Good clinician’s records are the most formidable weapon for the defense Documentation is vital, but it is useless without thorough his-tory taking Good records and good history taking put the responsibility on the patient’s honesty in response to the clinician

Document that the risks and benefi ts of all methods were discussed.

Document a plan for follow-up.

Document all interactions with the patient, including phone calls.

The Future

From 1970 to 1986, the number of births in women older than 30 drupled; from 1990 to 2005, the fertility rate among women older than 30 remained relatively stable, but in 2005 and 2006, the birth rates for women over 30 and for women over 40 increased.10,43,54 As couples deferred preg-nancy until later in life, the use of sterilization under age 35 declined, and the need for reversible contraception increased

qua-Until 2005, the highest number of births in the United States occurred between 1947 and 1965—the post–World War II baby boom (a demographic phenomenon shared by all parts of the developed world) Th e entire cohort

of women born in this period will reach their 45th birthday around 2010

We are in the midst, therefore, of an unprecedented number of women in

the later childbearing years Th is group of women is not only increasing in

number but is also changing its fertility pattern

Th e deferment of marriage is a signifi cant change in our society However, only a small percentage of the decline in the total fertility rate is accounted

for by the increase in the average age at fi rst marriage Most of the decline

in total fertility rate is accounted for by changes in marital fertility rates In

other words, postponement of pregnancy in marriage is the more signifi cant

change Th is combination of increasing numbers, deferment of marriage,

and postponement of pregnancy in marriage is responsible for the fact that

we are seeing more and more older women who will need reversible

contra-ception In short, there will continue to be a longer duration of contraceptive

use in younger women and greater use in older women, a pattern that began

in 1990

% Change 1985–2000

million

17.4 million

16.7 million

17.7 million

1988 and 1995, the use of oral contraceptives doubled among women aged

35 to 39 and increased 6-fold in women older than age 40.28 However, as the

previously mentioned statistics indicate, its use is still not suffi cient to meet

the need In addition to fulfi lling a need, this population of women has a

series of benefi ts to be derived from steroid contraception that tilt the risk/

benefi t ratio to the positive side (Chapter 2)

Th e growing need for reversible contraception would also be served by increased use of the IUD Th e decline in IUD use in the United States was

in direct contrast to the experience in the rest of the world, a complicated

response to publicity and litigation An increased risk of pelvic infection

with contemporary IUDs in use is limited to the act of insertion and the transportation of pathogens to the upper genital tract Th is risk is eff ectively minimized by careful screening with preinsertion cultures and the use of good technique A return to IUD use by American couples is both war-ranted and desirable

A major problem in the United States is the prevalence of tions More than half of women, even well-educated women, are not accu-rately aware of the effi cacy or the benefi ts and side eff ects associated with contraception.56–58 Unfortunately, a signifi cant percentage of women still do not know that there are many health benefi ts with the use of steroid contra-ception Misconceptions regarding contraception have, in many instances, achieved the stature of myths Myths are an obstacle to good utilization and can only be dispelled by accurate and eff ective educational eff orts

misconcep-Contraceptive advice is a component of good preventive health care Th e clinician’s approach is a key Th is is an era of informed choice by the patient

Patients deserve to know the facts and need help in dealing with the state

of the art and the uncertainty But there is no doubt that patients, especially young patients, are infl uenced in their choice by their clinicians’ advice and attitude Although the role of a clinician is to provide the education neces-sary for the patient to make proper choices, one should not lose sight of the powerful infl uence exerted by the clinician in the choices ultimately made

In the 1970s, we approached the patient with great emphasis on risk In the 1990s, studies eff ectively documented the risks and benefi ts of contracep-tion In the new century, the approach should be diff erent, highlighting the benefi ts and the greater safety of appropriate contraception If one attempts

to sum the impact of the benefi ts of contraception on public health, as some have done with models focusing on hospital admissions, there is no doubt that the benefi ts outweigh the risks Th e impact can be measured in terms

of both morbidity and mortality However, the impact on public health is of little concern during the clinician–patient interchange in the medical offi ce

Here personal risk is paramount, and compliance with eff ective tion requires accurate information presented in a positive, eff ective fashion

contracep-Th e challenge for the next 20 years is to do as Sherlock Holmes said: “You know my methods, use them.”59 A stable global population of about 8 to

10 billion is possible Without better contraceptive education and services, global population could reach 15 billion before stabilization

Useful Web Sites

13 Mueller TE, Gavin LE, Kulkarni A,

The association between sex education and youth’s engagement in sexual inter- course, age at first intercourse, and birth control use at first sex, J Adolesc Health 42:89, 2008.

14 Henshaw SK, Unintended pregnancy in

the United States, Fam Plann Perspect 30:24, 1998.

15 Lesher RL, Howick GJ, Assessing

technology transfer, NASA Report

No SP-50671, 1966.

16 Trussell J, Hatcher RA, Cates Jr W,

Stewart FH, Kost K, A guide to

inter-preting contraceptive efficacy studies, Obstet Gynecol 76:558, 1990.

17 Trussell J, Hatcher RA, Cates Jr W,

Stewart FH, Kost K, Contraceptive

fail-ure in the United States: an update, Stud Fam Plann 21:51, 1990.

18 Trussell J, Contraceptive efficacy of the

Reality® female condom, Contraception 58:147, 1998.

19 Trussell J, Vaughan B, Contraceptive

failure, method-related discontinuation and resumption of use: results from the

1995 National Survey of Family Growth, Fam Plann Perspect 31:64, 1999.

20 Kost K, Singh S, Vaughan B, Trussell

J, Bankole A, Estimates of contraceptive

failure from the 2002 National Survey

of Family Growth, Contraception 77:10, 2008.

21 Pearl R, Factors in human fertility

and their statistical evaluation, Lancet 222:607, 1933.

22 Fu H, Darroch JE, Haas T, Ranjit N,

Contraceptive failure rates: new mates from the 1995 National Survey

esti-of Family Growth, Fam Plann Perspect 31:58, 1999.

23 Chandra A, Martinez GM, Mosher WD,

Abma JC, Jones J, Fertility, family

plan-ning, and reproductive health of U.S

women: data from the 2002 National Survey of Family Growth, National Cen- ter for Health Statistics Series 23, No 25, 2005.

24 Mosher WD, Martinez GM, Chandra

A, Abma JC, Willson SJ, Use of

con-traception and use of family planning services in the United States: 1982–2002, National Center for Health Statistics Advance Data from Vital and Health Statistics, No 350, 2004.

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2 Oral Contraception

development in human history On the contrary, efforts to limit reproduction predate our ability to write about it It is only contra-ception with synthetic sex steroids that is recent

The History of Oral Contraception

It was not until the early 1900s that inhibition of ovulation was observed to

be linked to pregnancy and the corpus luteum Beginning in 1920, Ludwig Haberlandt, professor of physiology at the University of Innsbruck, Austria, demonstrated that ovarian extracts given orally could prevent fertility in mice

Haberlandt is acknowledged as the fi rst to perform experiments with the aim

of producing a method of hormonal contraception; he called it “hormonal sterilization.”1 In the 1920s, a Viennese gynecologist, Otfried Otto Fellner, conducting experiments in his spare time, and administering ovarian and pla-cental extracts to a variety of animals, also reported hormonal sterilization.2

By 1931, Haberlandt proposed the administration of hormones for birth trol An extract named Infecundin was produced in collaboration with the Hungarian pharmaceutical company Gideon Richter, but Haberlandt’s early death of a heart attack in 1932, at age 47, brought an end to this eff ort Fellner disappeared aft er the annexation of Austria to Hitler’s Germany

con-Th e concept was annunciated by Haberlandt, but steroid chemistry was not ready Th e extraction and isolation of a few milligrams of the sex ste-roids required starting points measured in gallons of urine or thousands of pounds of organs Edward Doisy processed 80,000 sow ovaries to produce

12 mg of estradiol

Russell Marker

Th e supply problem was solved by a cantankerous iconoclast, Russell E

Marker, who completed his thesis, but not the course work, for his Ph.D Th e following story is derived from Marker’s own words, in an autobiographi-cal article and from a 2-hour interview for the oral history archives of the Chemical Heritage Foundation in Philadelphia.3,4

Marker, born in 1902 in a one-room log cabin on a farm near Hagerstown, Maryland, received his bachelor’s degree in organic chemistry and his

master’s degree in colloidal chemistry from the University of Maryland

Although he had completed his work for a Ph.D., his supervisor, Morris

S Kharasch, announced that Marker still lacked some required chemistry

courses Considering the courses a waste of time, Marker said, “Th e hell

with it,” and abruptly left

Aft er leaving the University of Maryland, Marker worked fi rst in the oratory of the Naval Powder Factory, then with the Ethyl Gasoline Corpora-

lab-tion, where in 1926 he developed the system of octane rating of gasoline

Frank Whitmore, dean of Pennsylvania State College, now Pennsylvania

State University, visited Marker at Ethyl Impressed with his work,

Whit-more said, “If you’re ever looking for a job, let me know.”

From 1927 to 1934, Marker worked at the Rockefeller Institute, ing a total of 32 papers on confi guration and optical rotation as a method of

publish-identifying compounds He became interested in steroid chemistry, but he

was told to continue with his work in optical technology Instead, Marker

called Dean Whitmore at Penn State

In September 1935, Marker moved to Penn State at a reduced salary, from

$4,400 per year at Rockefeller to $1,800, but with the freedom to pursue any

fi eld of research His work was supported mainly by research grants from the

Parke-Davis pharmaceutical company At that time, it required the ovaries

from 2,500 pregnant pigs to produce 1 mg of progesterone Marker decided

to pursue the goal of an abundant and inexpensive supply of progesterone,

and for several years he concentrated on urine from pregnant animals Th en

in 1939, Marker devised the method, called the Marker degradation, to

con-vert a sapogenin molecule into a progestin

Marker was convinced that the solution to the problem of obtaining large quantities of steroid hormones was to fi nd plants in the family that includes

the lily, the agave, and the yam that contained suffi cient amounts of diosgenin,

a plant steroid, a sapogenin, that could be used as a starting point for steroid

hormone production He discovered that a species of Trillium, known locally

as Beth’s root, was collected in North Carolina for the preparation of Lydia

Pinkham’s Compound, popular at the time to relieve menstrual discomfort

A principal ingredient in Beth’s root was diosgenin, but the rhizome was too

small to provide suffi cient amounts for commercial production

Marker’s search for an appropriate plant took him to California, Arizona, and Texas Spending his summer vacations in the Southwest and Mexico

collecting sapogenin-containing plants, Marker’s laboratory analyzed more

than 100,000 lbs of over 400 diff erent species of plants Marker discovered

that the roots of the Dioscorea plant (a wild yam) were the richest source of

sapogenins

On a visit to Texas A & M University, Marker found a picture of a large

Dioscorea (Dioscorea mexicana) in a book that he just happened to pick

up and browse through while spending the night at the home of a retired

botanist who was helping him collect diosgenin-containing plants Aft er

returning to Pennsylvania, he traveled by train for 3 days to search for this

Dioscorea in Mexico.

Marker fi rst went to Mexico City in November 1941, but his eff ort was blocked by the lack of a plant-collecting permit from the Mexican govern-ment He returned in January 1942, and the American Embassy arranged for a Mexican botanist who had a collecting permit to accompany Marker to Veracruz Marker rented a truck with a driver, and when the botanist arrived

at Marker’s hotel, he was accompanied by his girlfriend and her mother, who served as the girl’s chaperone Marker was forced to take the entire group

Th ey covered 80 miles the fi rst day, staying overnight in Puebla Th e next day, the drive to Tehuacan was a shorter trip, but the botanist insisted on

a 2-day stay devoted to his own collection of specimens Th en next ing, the botanist refused to go any further, claiming that the natives had discovered Marker was American and wanted nothing to do with him Th ey turned around, managed to overcome a breakdown of the truck near Puebla, and made it back to Mexico City 5 days aft er starting, with nothing to show for the trip

Embassy and was advised to leave Mexico It was just aft er Pearl Harbor and Mexico was being courted by Germany Th e Embassy was concerned for the safety of Americans traveling in Mexico Instead of returning home, Marker took an overnight bus to Puebla, arriving aft er midnight, and boarded a sec-ond bus that already held pigs and chickens in addition to a few passengers

He arrived in Orizaba the next morning, and fortunately there was a small hotel next to the bus terminal Marker remembered that the botany book

in which he fi rst read a description of D mexicana indicated that the plant,

a wild yam vine that grows up trees in the mountains of southern Mexico, could be found along a stream that crossed the road between Orizaba and Cordoba He climbed aboard the local bus to Cordoba, which he stopped and disembarked when the bus drove through a large stream crossing the road about 10 miles aft er leaving Orizaba He found a small country store next to the road, owned by an Indian named Alberto Moreno

Moreno did not speak English; Marker did not speak Spanish But

some-how, Marker conveyed his desire to obtain the Dioscorea that was known

locally as “cabeza de negro,” black tubers Moreno in turn somehow made Marker understand that he should return the next morning And there in the store, the next morning, were two plants, each in a bag that Moreno placed on the roof of the next bus back to Orizaba Each tuber was 9 to 12

in long and consisted of white material like a turnip; it was used by local Mexicans as soap and as a poison to catch fi sh When Marker got off the bus

in Orizaba, both bags were missing A policeman was there, but it became apparent he was there to collect a fee for the return of the bags Marker gave him what he had, a 10-dollar bill, but that only retrieved one bag, which he managed to smuggle back to Pennsylvania

Marker used only a portion of the plant to isolate diosgenin In February

1942, he took the remainder to the Parke-Davis chemists in Detroit onstrating his process for obtaining diosgenin, Marker convinced the direc-tor of research, Oliver Kamm, that he was on to something, a source for raw

material that could provide for the commercial production of hormones

Unfortunately, they could not convince the president of Parke-Davis, nor

could Marker convince anyone at several other companies

Unable to obtain support from the pharmaceutical industry, Marker, drew on half of his life savings and returned to Mexico in October 1942

He arranged with Albert Moreno to collect the roots of the Mexican yam

Marker paid Mexican medical students to collect the yams Th e students

were arrested when farmers reported that their yams were being stolen, but

not before Marker had enough to prepare a syrup

Back in the United States with his syrup, Marker arranged to work in the New York laboratory of a friend, Norman Applezweig, an organic chemist

involved in steroid research, in return for one-third of whatever

progester-one his syrup could yield.5 He isolated diosgenin and synthesized 3 kg of

progesterone, the largest lot of progesterone ever produced United States

pharmaceutical companies still refused to back Marker, and even his

univer-sity refused, despite Marker’s urging, to patent the process

Before Marker left Mexico, he looked through the yellow pages in a ico City telephone directory and found something he recognized, a company

Mex-called “Laboratorios Hormona,” owned by a lawyer who was a Hungarian

immigrant, Emeric Somlo, and a German immigrant who had both a

medi-cal degree and a Ph.D in chemistry, Frederick A Lehman

… when the phone rang A distant voice asked in barely comprehensible Spanish if he {Frederick Lehman} spoke English

“Yes, of course.”

“I found your company’s name in the telephone book, since I recognized two words, ‘Laboratories’ and ‘Hormones.’ I have something you may

be interested in: a cheap source for progesterone.”

“Who are you?”

“I am Marker, a steroid chemist.”6

Visiting the company, Marker met Lehman, the minority owner of

Labora-torios Hormona, who had the good sense to see where this was going From

his reading of the literature, he knew who Marker was; he knew the value of

steroids; and he was a businessman Lehman called his partner who was

vis-iting New York and convinced him to return as soon as possible Th e three

men agreed to form a Mexican company for the production of hormones,

and Marker returned to the United States, leaving behind a list of equipment

and chemicals to be ordered

Marker returned to Mexico in spring 1943 to collect plants and to check

on progress at Laboratorios Hormona He just happened to mention to

Leh-mann that he had 2 kg of progesterone As soon as Marker returned to

Penn-sylvania, he received a phone call from Somlo who said that if Marker still

had those 2 kg of progesterone he sure would like to see it; could he meet him

in New York? Over dinner at the Waldorf-Astoria, Somlo off ered Marker

40% of their new company in exchange for the progesterone, with a share

in future profi ts Marker arranged for a friend to deliver the progesterone

to Somlo in New York Somlo had a small company in New York called Chemical Specialties, and the progesterone used in the fi rst studies leading

to oral contraception was obtained from this Syntex subsidiary

In December 1943, Marker resigned from Pennsylvania State College

and went to Mexico where he collected the roots of D mexicana—10 tons

worth! Marker chopped them up with a machete, and left the pieces to dry

in the sun across from Moreno’s store in a small structure for drying coff ee

It took 2 months of work in an old pottery shed in Mexico City to prepare several pounds of progesterone, worth $160,000, with the help of several young women who had little education and spoke no English

Somlo suggested calling their new company Synthesis, but Marker insisted on some link to Mexico, and the three partners formed Syntex

(from synthesis and Mexico), incorporated in March 1944 Marker moved

into a new four-room laboratory, and over the next year, produced over

30 kg of progesterone and 10 kg of dehydroepiandrosterone Th e price of progesterone fell from $200 to $50 a gram

During this time, Marker received expenses, but he was not given his share of the profi ts or the 40% share of stock due to him In March 1945, Somlo claimed there were no profi ts, but then admitted that the profi ts had been paid to the two partners in Mexico as salaries Failing to reach a settle-ment, Marker left Syntex in May 1945, took some of his young female work-ers with him, and started a new company in Texcoco, called Botanica-Mex

He changed to Dioscorea barbasco, which gave a greater yield of diosgenin,

and the price of progesterone dropped to $10 a gram, and later to $5

Aft er I broke up with Lehmann and Somlo, I chose a place east of Mexico City (Texcoco), where labor and water were plentiful I there repeated

my simple procedure of converting diosgenin into progesterone My workers were happy but one day they came to me and said, “We all live on this dry-lake bed, and we come from very far away If you want

us to go on working for you, we need bicycles.” “Sure,” said Marker,

“I’ll buy them for you, and you will pay them back from your salary.”

Th e workers, happy with this off er, and the image of a white man with promise, celebrated drunkenly one evening Late at night they went

to a nearby quarry where a great effi gy of the Aztec rain god was still attached by its back to the bedrock (It wasn’t moved to the museum until 1964) Th ey then began chiseling my name over Tláloc’s right eyebrow, but were interrupted by angry villagers and had to run away aft er having carved only the fi rst two letters.3

Th e volcanic stone monolith of Tláloc the rain god was carved in a zontal position sometime in the period of 400 B.C to 200 A.D On April 16,

hori-1964, the unfi nished statue was detached and transported on a day’s ney to Mexico City, and placed in a vertical position at the road entrance

jour-to the Museo Nacional de Antropologia, an imposing 168 jour-tons, 23 ft high

Th e initials “MA” can be easily discerned at the right edge of the headdress;

Marker’s workers obviously intended to place his full name across the entire

width Th e evening arrival of the rain god was greeted by a crowd of 25,000

people Despite the fact that it was the dry season, a record rainfall fell on

the day the statue arrived!7

Marker’s new company was allegedly harassed, legally and physically, by Syntex, and in 1946 it was sold to Gideon Richter, which moved it to Mexico

City and renamed it Hormosynth Eventually it came under the

owner-ship of Organon of Holland, which still uses it under the name of Quimica

Esteroides By the 1960s, several pharmaceutical companies were benefi ting

from the root-gathering operations in Mexico, closely regulated by the

Mex-ican government that imposed annual quotas, about 43,000 tons, to balance

harvesting with the new annual growth Mexican yams provided the starting

material for the manufacture of oral contraceptives for about 15 years,

giv-ing way to other sources, such as soya beans, methods for total synthesis, or

microbial fermentation.8

In 1949, Marker retired to Pennsylvania to devote the rest of his life to traveling, and in 1959 he began an association with a French silversmith who

had emigrated to Mexico City, and then with his son, Pedro Leites Aft er

1970, Marker turned to collecting paintings by Mexican artists Th e artwork

and the replicas of antique works in silver were successful businesses that

allowed him, in the 1980s, to endow scientifi c lectureships at both

Pennsyl-vania State University and the University of Maryland In 1970, the Mexican

government honored Marker and awarded him the Order of the Aztec Eagle;

staying true to his irascible nature, he declined In 1984, Pennsylvania State

University established the annual Marker Lectures in Science and, in 1987,

the Russell and Mildred Marker Professorship of Natural Product

Chemis-try In 1987, Marker was granted an honorary doctorate in science from the

University of Maryland, the degree he failed to receive in 1926

In 1990, Marker was planning on a quiet visit to Mexico to present a plaque made in his honor by Pennsylvania State University to Adolfi na Moreno, the

daughter of Alberto, the owner of the small country store whom Marker met

in 1942 Mexican scientists and pharmaceutical people learned of the visit,

and that summer a chartered busload of fi ft y people retraced Marker’s trip

from Mexico City to Orizaba.6 Marker rode in a car with Frederico Lehman’s

son, Pedro, who had become a distinguished chemist Meeting in an

audito-rium at the University of Veracruz, Marker was honored by speeches and an

engraved silver tray Aft er lunch at a local brewery, nearly 100 people made

their way to the bridge over the Mezcala River Marker entered the living

quarters behind the store now owned by Adolfi na She tearfully thanked him

and pointed to a nearby photo, her marriage picture from 50 years ago, with

Marker in the wedding group At the age of 92, Russell Earl Marker died in

Wernersville, Pennsylvania, in 1995, from complications aft er a broken hip

The Race for Cortisone

When Marker left Syntex, he took his know-how with him Fortunately for

Syntex, there still was no patent on his discoveries George Rosenkranz left

his native Hungary to study chemistry in Switzerland under the renowned

steroid chemist Leopold Ruzicka, who was awarded the 1939 Nobel Prize

in Chemistry.9 On the day Pearl Harbor was attacked, Rosenkranz was in Havana waiting for a ship to Ecuador where the chair in organic chemistry awaited him at the University of Quito Th e ship never showed Rebuff ed by the national university in Cuba, Rosenkranz took a job with a local phar-maceutical fi rm for $25 per week Because of his success in developing new products, he was soon earning $1,000 per month and directing a research program with Ph.D candidates from the university He was also learning how to be a business man; for example, he organized the shark-fi shing busi-ness in Cuba in order to produce vitamin A from shark liver oil.10

Th e Rosenkranz laboratory was following Marker’s published techniques and making small amounts of progesterone and testosterone from sarsapa-rilla roots imported from Mexico Th e news of this activity led to an invita-tion from Syntex to take over for Marker, with an option of buying 15% of Syntex stock, although the company was currently practically bankrupt

Rosenkranz’s task was complicated by Marker’s secretiveness He found reagents labeled with code words; Marker’s workers identifi ed solvents by their weight and smell Rosenkranz gave up on reconstructing Marker’s pro-cess, and worked out his own commercial manufacture of progesterone and testosterone from Mexican yams, and soon Syntex was making large profi ts providing the sex hormones as raw material to other pharmaceutical com-panies Rozenkranz now had a large active laboratory that attracted a young chemist, Carl Djerassi Th ese men knew each other, meeting and interacting with each other at the Laurentian Hormone Conference, the annual meeting organized and directed by Gregory Pincus

Th e Djerassi family lived in Bulgaria for hundreds of years aft er escaping Spain during the Inquisition.11 Carl Djerassi, the son of a Bulgarian physi-cian, was born in Vienna, as was his physician mother Djerassi, age 16, and his mother fl ed the Nazi Anschluss and emigrated to the United States in

1939 A Jewish refugee aid organization placed Djerassi with a family in Newark, New Jersey With a scholarship to Tarkio College in Tarkio, Mis-souri, he was exposed to Middle America, where he earned his way giving talks to church groups about Bulgaria and Europe His education was fur-ther supported by another scholarship from Kenyon College in Ohio, where

he pursued chemistry Aft er a year working for CIBA, Djerassi received his graduate degree from the University of Wisconsin Returning to CIBA and being somewhat unhappy, he responded to an invitation to visit Syntex

Rosenkranz proposed that Djerassi head a research group to concentrate on the synthesis of cortisone Djerassi’s initial reaction was that “the location of Syntex in the chemical desert of Mexico made the off er seem ludicrous.”12

But the 26-year-old Djerassi, impressed by Rosenkranz and excited by the challenge to develop a method to synthesize cortisone, accepted the position and moved to Mexico City in the fall of 1949

Earlier in 1949, Philip S Hench, a Mayo Clinic rheumatologist, showed a movie at a medical meeting documenting crippled arthritic patients before treatment and the same patients active, even dancing, aft er daily injections

with cortisone Cortisone can be converted to the more active cortisol (also

called hydrocortisone), the major product of the adrenal cortex Cortisone

is produced by hydroxylation, which converts the oxygen attached at the

11 position to a hydroxyl group by adding a hydrogen

Hench had obtained the very expensive cortisone through a biochemist

at the Mayo Foundation, Edward C Kendall, the discoverer of the thyroid

hormone, thyroxine, who had been working with Lewis H Sarett at Merck &

Company to determine the structures of compounds isolated from extracts

of the adrenal cortex and from cattle bile; cortisone was known as Kendall’s

Compound E Hench reported good results in 14 patients; his movie received

Nobel Prize in Physiology or Medicine It was recognized that continuing

regular treatment would be necessary, and the race was on to develop an

easy and cheap method to synthesize cortisone and related drugs

In Mexico City, Carl Djerassi was using the plant steroid diosgenin from the Mexican yam as the starting point In 2 years’ time, Syntex achieved the

partial synthesis of cortisone, reported in 1951.14 Th e Syntex method never

reached commercialization, however, because a more effi cient process was

developed by the Upjohn Company Djerassi’s productivity at Syntex, 60

pub-lications, attracted a job off er from Wayne State University.15 Wanting all along

to be in the academic world, Djerassi moved to Detroit in January 1951 Five

years later, he took a leave of absence to return to Syntex, now

American-owned and a public company Syntex’s topical corticoid anti-infl ammatory

products, Synalar and Neosynalar, came from Djerassi’s laboratory Djerassi

maintained his laboratory at Wayne State, and in 1959, when W.S Johnson at

Wisconsin moved to head the chemistry department at Stanford University,

Djerassi joined him—a professorial position he held for the next 25 years

Th e Upjohn Company and G.D Searle & Company joined the tition to synthesize cortisone, with Upjohn, the bigger company, devoting

compe-over 150 scientists and technicians to the task Upjohn leadership assigned

a symbol to represent the project, a blow torch, making it clear that this was

a heated race they wished to win.16 G.D Searle was a smaller company, but

its participation in this race would cement a long-term relationship with

Gregory Pincus

G.D Searle was founded in 1888 by Gideon Daniel Searle, a cist in Indiana, to provide elixirs, syrups, and drugs directly to clinicians

pharma-Searle’s son, Claude, graduated from Rush Medical College in 1898 and

developed a large, successful practice in Sabula, Iowa In 1909, when his

father suff ered a stroke, the son returned to Chicago to manage the

com-pany, setting up a research department that developed new products His

son, Jack Searle, graduated from the University of Michigan with a degree

in pharmacy, and succeeded his father as president of the company in 1936

He recruited Albert L Raymond from the Rockefeller Institute to serve as

director of research, working in new laboratories in Skokie, Illinois

Drama-mine, to prevent motion sickness, and Banthine, to treat peptic ulcers, came

from these laboratories

By 1949, Raymond and the G.D Searle company were supporting steroid research at the Worcester Foundation for Experimental Biology in Massa-chusetts, and Gregory Pincus, the cofounder of the Worcester Foundation, was a Searle consultant.17 Pincus and Oscar Hechter had developed a perfu-sion method, pumping blood, serum, or a serum-like solution through fresh endocrine glands (adrenal glands, testicles, or ovaries) held in a glass appa-ratus and collecting the perfused fl uid Using the enzymes in the glands, precursors in the perfusing fl uid were converted to the fi nal products, hydrocortisone or the sex steroids Th is was a method that could be used to produce commercial amounts of cortisone products

Th e round-faced, balding, acerbic Oscar Hechter came to the Worcester Foundation in 1944 on a fellowship funded by G.D Searle Pincus assigned him the task of perfusing adrenal glands, with the aim of identifying the products of adrenal secretion and the hope of creating a system for com-mercial production Five years later, Hechter presented the fi rst positive results at a conference in Detroit in 1949.18 At that same meeting, Hechter saw Hench’s movie and listened to his results Hechter returned to the Foun-dation and urged that his project be given top priority Pincus’s enduring relationship with Searle that yielded research support and new steroid com-pounds for almost never-ending testing began in earnest with the race for cortisone and his development of the perfusion system to use animal glands for the synthesis of steroid drugs Th e perfusion system was complicated

It required the development of methods to maintain the animal organs, a web of glassware to infuse and collect appropriate perfusing solutions, and the separation and identifi cation of the steroid products At the moment of its coveted value in 1946, Pincus chose to sell his rights to Searle for only

1 dollar, allowing Searle to patent the process.19 In return, Pincus obtained and tested steroids that could yield products for clinical use

Responding to Pincus and Hechter’s success, the Searle company structed rows of perfusion systems in their Skokie plant Each contained a periodically replaced fresh beef adrenal gland, producing every few hours

con-a lcon-arge volume of perfused solution Th e long-term plan was to engineer a more economical and profi table system But in the meantime, Searle was able to provide substantial amounts of cortisone to clinical researchers throughout the United States

At the same time, Merck ramped up Sarett’s 36-step synthesizing process from bile acids, and by the end of 1950, they were selling cortisone acetate

to clinicians for a price that had been reduced from $200 per gram to $35 In Kalamazoo, Michigan, Upjohn chemists were pursuing a method based on the process used to make penicillin, conversion of precursors by microbes to the desired product Th e work was headed by Durey H Peterson, the son of Swedish immigrants Peterson supported his education by playing semipro-fessional baseball.16 Early in his career, he developed nylon surgical suturing material as well as “Toni,” a product for home permanents to create curly hair Peterson joined Upjohn in 1946 to work on antibiotics, but he almost

believed that lower microorganisms might possess the same enzymes used

by adrenal glands to make cortisone, especially the diffi cult step of

introduc-ing an oxygen molecule to the structure When told this could not be done,

Peterson said, “Th e microorganisms do not know this.”16

Using paper chromatography methods developed by Alejandro Zaff aroni, Peterson and H.C Murray attacked the problem, beginning in 1949 First

they needed a microorganism Th is they acquired, a fungus of the Rhizopus

species, by leaving an agar plate on the window sill of the “oldest and

dirti-est laboratory at the Upjohn Company.”16 In 1 year’s time, the two chemists

proved the value of microorganisms in chemical synthesis Th eir method

used Rhizopus nigricans to covert progesterone to 11-hydroxyprogesterone,

that could in turn be processed into hydrocortisone, also called cortisol, the

major corticosteroid secreted by the adrenal cortex

By 1955, Upjohn had become the market leader, and Searle shut down its perfusion cells and quit the race Upjohn’s commercialization of the methods

developed by Peterson and Murray led to popular and successful products

But the Searle people had gained valuable experience that would eventually

pay off with other synthesized hormones and products

Th e Upjohn method used progesterone as the starting point, available in the early 1950s only from Syntex George Rosenkranz’s laboratory at Syntex

was also pursuing the industrial synthesis of cortisone, and in July 1951,

Syn-tex was about to sign a contract with a large chemical fi rm to begin

produc-tion Th is never happened because of a phone call Rosenkranz told the story:

“I received a phone call from Upjohn asking me whether we would be able to

accept an order for 10 tons of progesterone at 48 cents a gram.”10 Th e quantity

was unheard of, and Upjohn’s order remained a puzzle until the

microfer-mentation method was published Rosenkranz accepted the order, and

Syn-tex found itself as the key supplier of progesterone to other companies

The Synthetic Progestational Drugs, Norethindrone

and Norethynodrel

Djerassi and other Syntex chemists turned their attention to the sex steroids

Th ey discovered that the removal of the 19-carbon from yam-derived

pro-gesterone increased the progestational activity of the molecule Th e clue for

this work came from Maximilian Ehrenstein at the University of

Pennsyl-vania, who reported in 1944 that a potent progestational compound he had

produced appeared to be progesterone without its carbon at the 19

posi-tion; henceforth, the 19-nor family of compounds indicated steroid

chem-ical structures without the carbon atom at the 19 position.20 Chemists at

Schering A.G in Berlin had produced orally active versions of estradiol and

testosterone in 1938, by substituting an acetylene group in the 17-position

of the parent compounds Th e resulting ethinyl estradiol later became the

estrogen component in oral contraceptives Th e ethinyl testosterone

prod-uct was known as ethisterone, marketed in 1941, and the Syntex chemists

reasoned that removal of the 19-carbon would increase the progestational

potency of this orally active compound

On October 15, 1951, norethindrone was synthesized at Syntex; the fi nal steps were performed by Luis Miramontes, working on his undergraduate thesis in chemistry under Djerassi’s supervision.12 Th e patent application was

fi led 6 weeks later on November 22, 1951, and the work was presented in April 1952 at the annual meeting of the American Chemical Society and pub-lished in 1954.21 Th e greater potency of norethindrone, achieved by remov-ing the 19-carbon of ethinyl testosterone, compared with progesterone was demonstrated in monkeys and then four women at the National Institutes

of Health, reported in 1953, 1956, and 1957.22–24 Syntex supplied drone to many investigators, including Gregory Pincus Edward T Tyler fi rst reported its clinical use in 1955 for the treatment of menstrual disorders.25

norethin-Frank Colton, a chemist at G.D Searle & Company, fi led a patent for norethynodrel, a compound closely related to norethindrone, diff ering only

in the position of the double bond, on August 31, 1953 Th e Polish-born Colton received his Ph.D in chemistry from the University of Chicago

From 1949 to 1951, he was a research fellow working with Edward Kendall

at the Mayo Foundation on the synthesis of cortisone Colton joined Searle

in 1951, along with Byron Riegel, to develop steroid drugs, succeeding with Nilevar, the fi rst commercial anabolic agent marketed in 1956 and Aldac-tone, the antialdosterone antihypertensive agent introduced in 1959

Norethynodrel was the result of a deliberate and planned program to ate orally active agents with progestational activity Later, Colton pointed out that although the Syntex and Searle chemists followed a similar path, they were independently pursuing the trail blazed by previous scientists.17 Along the way, hundreds of compounds were sent to Pincus at the Worcester Foun-dation to test for ovulation inhibition in rabbits Th eir best drug, norethyno-drel, assigned the number SC-4642, was synthesized at Searle in a process that was considered to be signifi cantly diff erent from the Syntex method.17

cre-Djerassi urged legal proceedings for patent infringement, claiming that norethynodrel was converted to Syntex’s compound, norethindrone, by gas-tric acid, but Parke-Davis, the American company licensing norethindrone, did not want to make waves presumably because Parke-Davis was supplying the antihistamine component of Searle’s best-selling product for motion sick-ness, Dramamine.12 Pincus would ultimately choose the Searle compound, norethynodrel for clinical testing as an oral contraceptive, and Syntex, not having marketing capability, licensed norethindrone to other pharmaceuti-cal companies Norethindrone was tested as a contraceptive by Edward Tyler

in Los Angeles and Joseph Goldzieher in San Antonio, Texas, but Davis chose not to pursue government approval, probably fearing religious reactions Subsequently, Syntex turned to the Ortho division of Johnson &

Parke-Johnson By 1964, Ortho, Parke-Davis, and Syntex (now in California) were marketing oral contraceptives containing norethindrone or its acetate

Th e creation of norethindrone and norethynodrel by the chemists was essential in the development of oral contraception because the natural hor-mone progesterone is relatively impotent given orally, requiring very large

progestational agents are very active when administered orally, producing

reliable eff ects with small doses

A Wall Street entrepreneur, Charles Allen, acquired Syntex in 1956 for

$2 million cash and a loan of $2 million to be paid from future profi ts.9

Rosenkranz became president and CEO, Alejandro Zaff aroni, an Italian who

emigrated from Montevideo, Uruguay, executive vice president Zaff aroni

obtained his Ph.D in 1949 in biochemistry from the University of

Roches-ter, developing a paper chromatography system that soon became a

princi-pal method of studying steroid hormones.26 Rosenkranz met Zaff aroni at

the Laurentian Hormone Conference in 1951 Th eir aim was to develop a

pharmaceutical company on a foundation of research Carl Djerassi, who

had left for an academic position at Wayne State University, was recruited

back to the company Rosenkranz said, “We were the brilliant amateurs with

a ‘can do anything’ attitude We were like stem cells (though then none of us

really knew the concept) We could diff erentiate into anything we desired

Production, fi nance, sales, marketing—all held no fear for us.”9

In 1961, the company moved to Palo Alto, California, infl uenced by Djerassi who was teaching at Stanford University Th e growth of the company

was meteoric, with blockbuster hits like Synalar, a topical corticoidsteroid

for the treatment of psoriasis, and Naproxen, a nonsteroid, anti-infl

am-matory drug Much of this success was to an innovative philosophy in the

pharmaceutical business, “patent and publish.”9 Th e Syntex scientists were

encouraged to promptly publish their results, gaining the peer recognition

that is such a motivating force for basic scientists In 1994, Roche Holdings

acquired Syntex for $5.3 billion

Djerassi eventually left Syntex to become a full-time professor at Stanford University, and is now a playwright and novelist living in San Francisco

Zaff aroni started his own company in 1968, ALZA (aft er his own name),

dedicated to new methods of drug delivery, such as a skin patch ALZA was

acquired by Johnson & Johnson in 2000

Gregory Pincus

Gregory Goodwin (Goody) Pincus was born in 1903 in New Jersey, the son

of Russian Jewish immigrants who lived on a farm colony founded by a

Jew-ish philanthropic organization.19 Pincus was the oldest of six children and

grew up in a home of intellectual curiosity and energy, but even his family

regarded him as a genius

Pincus graduated from Cornell and went to Harvard to study ics, joining Hudson Hoagland and B.F Skinner as graduate students of

genet-W.J Crozier in physiology, receiving degrees in 1927 Crozier’s hero was

Jacques Loeb who discovered artifi cial parthenogenesis working with sea

urchin eggs Most importantly, Loeb was a strong believer in applying

sci-ence to improve human life Th us, Crozier, infl uenced by Loeb, taught

Pin-cus, Hoagland, and Skinner (in reproductive biology, neurophysiology, and

psychology, respectively) to apply science to human problems Th is was to

be the cornerstone of Pincus’s own philosophy

Hoagland, aft er a short stay at Harvard, spent a year in Cambridge, England, and then moved to Clark University in Worcester, Massachu-setts, to be the chair of biology at the age of 31 Pincus went to England and Germany, and returned to Harvard as an assistant professor of physiology

Pincus performed pioneering studies of meiotic maturation in lian oocytes, in both rabbit and human oocytes In 1934, Pincus reported the achievement of in vitro fertilization of rabbit eggs, earning him a head-

mamma-line in the New York Times that alluded to Haldane and Huxley An article

in Colliers depicted him as an evil scientist By 1936, Harvard had cited

Pincus’s work as one of the university’s outstanding scientifi c achievements

of all time, but Harvard denied him reappointment in 1937

At Clark University, Hudson Hoagland was in constant confl ict with the president of the university, Wallace W Atwood, the senior author of a widely used textbook on geography In 1931, the Department of Biology consisted

of one faculty member and his graduate student, and their chair, Hudson Hoagland Hoagland, upset and angry over Harvard’s refusal to grant reap-pointment to his friend (suspecting that this was because of anti-Semitism), invited Pincus to join him Hoagland secured funds for Pincus from philan-thropists in New York City, enough for a laboratory and an assistant Th is success impressed the two men, especially Hoagland, planting the idea that

it would be possible to support research with private money

Min-Chueh Chang was born in Tai Yuan, China, on October 10, 1908

In 1933, he earned a bachelor’s degree in animal psychology from the Tsing Hua University in Peking and stayed at the university as a teacher Chang won a national competition in 1938 that funded study abroad He chose

to study agricultural science at Edinburgh University Aft er 1 year, he was pleased to receive an invitation from Arthur Walton to study the physi-

accepted

Chang received his Ph.D in animal breeding under the direction of Walton and Sir John Hammond at the University of Cambridge in 1941 It was virtually impossible to leave England during the early years of World War II, and Chang continued to work at the University In 1944, Chang planned to return to China, but fi rst he wanted to spend a year in the United States He wrote three letters to American scientists, and only Pin-cus answered, off ering a fellowship at Clark University Chang mistakenly assumed that a fellowship in the United States was the same as at the Uni-versity of Cambridge where a Fellow was assured of a lifetime income Th e successful recruitment of Chang by Pincus was to pay great dividends Years later, Chang would direct the testing of new progestins to eff ectively inhibit ovulation in animals

Soon Hoagland had put together a group of outstanding scientists, but because of his ongoing antagonism with President Atwood, the group was denied faculty status Working in a converted barn, they were totally sup-ported by private funds By 1943, 12 of Clark’s 60 faculty were in the Depart-ment of Biology

Frustrated by the politics of academia, Hoagland and Pincus (who both enjoyed stepping outside of convention) had a vision of a private research

center devoted to their philosophy of applied science Indeed, the

establish-ment of the Worcester Foundation for Experiestablish-mental Biology, in 1944, can be

attributed directly to Hoagland and Pincus, their friendship for each other,

and their confi dence, enthusiasm, ambition, and drive It was their spirit

that turned many members of Worcester society into fi nancial supporters

of biologic science Hoagland and Pincus accomplished what they set out to

do Th ey created and sustained a vibrant, productive scientifi c institution in

which it was a pleasure to work

Although named the Worcester Foundation for Experimental Biology, the Foundation was located in the summer of 1945 across Lake Quinsiga-

mond in a house on an estate in Shrewsbury From 1945 to the death of

Pincus in 1967, the staff grew from 12 to 350 (scientists and support people),

36 of whom were independently funded and 45 were postdoctoral fellows

Th e annual budget grew from $100,000 to $4.5 million One hundred acres

of adjoining land were acquired, and the campus grew to 11 buildings In

its fi rst 25 years, approximately 3,000 scientifi c papers were published

But in those early years, Pincus was the animal keeper, Mrs Hoagland the bookkeeper, Chang was the night watchman, and Hoagland mowed the

lawn During the years of World War II, Pincus and Hoagland combined

their interests in hormones and neurophysiology to focus on stress and

fatigue in industry and the military

Katharine Dexter McCormick (1875–1967) was a trained biologist, an early suff ragist, and rich, inheriting millions from her mother and a McCormick

fortune from her husband She was the second woman to graduate from the

Massachusetts Institute of Technology, socially conscious, and a generous

contributor to family planning eff orts Her intervention with money, energy,

incisive thinking, and persistent dedication was instrumental in the

develop-ment of oral contraception In 1904, she married Stanley McCormick, the

son of Cyrus McCormick, the founder of International Harvester Katharine’s

husband suff ered from schizophrenia, and she established the

Neuroendo-crine Research Foundation at Harvard to study schizophrenia Th is brought

her together with Hoagland, who told her of the work being done by Chang

and Pincus who were seeking orally active progestins to inhibit ovulation

Pincus attributed his interest in contraception to his growing tion for the world’s population problem, and to a 1951 visit in New York with

Margaret Sanger, at that time president of the Planned Parenthood Federation

of America Sanger promised a small amount of money and expressed hope

that a method of contraception could be derived from the laboratory work

being done by Pincus and Chang During this meeting, Pincus formulated his

thoughts derived from his mammalian research He envisioned a progestational

agent in pill form as a contraceptive, acting like progesterone in pregnancy

Margaret Sanger brought Pincus and Katharine McCormick together On June 7, 1953, when 78-year-old Katharine met with 50-old Pincus at the

Worcester Foundation and wrote him a check for $20,000; she promised him