The
acceptance of the hormonal contraceptive pill has been cited as one
of the most important historical events of the 20th century because
of its effects on marriage and family life. In this paper, I would
like to discuss the medical history of the development of the pill,
presenting historical events primarily from the perspective of
science and scientists, but also – and necessarily – from the
perspective of other personalities outside of science whose
contributions to the cause were just as important.

I will focus on the 50 year period from 1910 – the year of the
birth of reproductive endocrinology as a scientific discipline – to
1960 – the year in which the first orally active hormonal
contraceptive was first approved for sale to the general public in
the US.

At the turn of the 20th century, there was growing confidence in
the power of the medical sciences to finally understand human
physiology and the patho-physiology of diseases. The source of this
confidence was due in no small part to advances in the field of
endocrinology: the study of hormones and the glands that produce
them.

The term "hormone" was coined in 1905 by the British
physiologist Ernest Starling, after the Greek word meaning "to
incite to activity". In the early 20th century, a variety of
chemicals were found to have "hormonal" effects in humans:
they were produced in one tissue, entered the bloodstream and incited
a specific effect on another distant and unrelated tissue. Insulin,
thyroxine,testosterone and cortisone were discovered at this time and
were found to have remarkable restorative properties when given to
patients with a number of common diseases.

This enthusiasm for the therapeutic potential of "hormones"
also extended to the area of human reproduction In the late 19th
century, Professor Brown-Sequard, at the age of 72, injected himself
with the extracts of guinea pig testicles and was astounded at their
rejuvenating effects.

Between 1910 and 1930, the hormones estrogen and progesterone were
found to play important roles in the physiology of female mammalian
reproduction, and so by around 1940, it became apparent that in human
females, fertility depended upon the complex interactions of a
hierarchy of hormones which affected the ovaries first, and then the
uterus. The ovaries were found to be the source of a "female
factor" in human development (the ova or egg):complementary to
and just as necessary for human reproduction as the"male
factor". This picture -- which seems so clear today -- was in
fact a dramatic insight, considering that even in the second half of
the 19th century many scientists still believed that conception
occurred when the male factor – a seed – was sown into the female
womb– the soil. A woman’s contribution to conception was thought
to be that off a passive receptacle offering a favorable environment
for the germination of the seed.

The picture that now emerged meant that fertility in women was in
the normal case orderly and cyclical, and therefore predictable. This
new understanding of human reproduction seemed to lift the veil on an
awesome event that, until then, had been shrouded in mystery. Science
began to expose the mystery, to reveal the mechanics of how human
beings came about, and made that event accessible and open to
manipulation.

Controlling fertility

The
notion that fertility in mammals could be controlled by the
manipulation of reproductive hormones was first proposed by the
Austrian physiologist Ludwig Haberlandt, who based his hypothesis on
his own work with laboratory animals He and others observed that the
ovarian follicle would not mature and ovulation would not occur
during normal pregnancy, and that this suppressive effect was
mediated by progesterone. Progesterone is produced by the corpus
luteum during the second half of thenormal menstrual cycle, and its
blood levels remain elevated only ifpregnancy occurs. As long as
certain levels of progesterone persist in the circulation, hormonal
signals favoring the ripening of additional ovarian follicles,
thickening of the endometrium and release the ova, would not occur.

So scientists like Haberlandt, who would seek to develop a birth
control pill, focused their efforts on finding a chemical that would
mimic the normal effects of progesterone. In effect, they sought a
chemical that would induce a pseudo-pregnant state Haberlandt was
probably the first to propose that "hormonal sterilization"
-- which he had successfully induced in several animal models --
could and should be applied to humans. He even developed a
progestin-based oral contraceptive which – a few decades after his
death in 1932 – was studied and distributed as the contraceptive
"Infecundin" in Eastern Europe by Marxist governments. His
original observations on the contraceptive potential of progesterone
in animals proved to be of use to others years later in planning
strategies for control of human fertility.

Overcoming cultural and religious hurdles

Before
moving on with the story,a brief digression: it is worth noting that
while scientists were unraveling the mysteries of human reproduction,
cultural attitudes during the first half of the 20th century strongly
discouraged public discussion of sexual matters, and many -- if not
most -- people agreed that the use of contraceptive devices was
somehow wrong. In many states, dispensing contraceptives or
information about them was a felony So advocates of the birth control
pill had to overcome not only important scientific hurdles but also
widely held cultural and religious objections. There was the clear
perception among early advocates of birth control that acceptance of
a contraceptive pill would be difficult to achieve.

Margaret Sanger led the campaign in the US that would gradually --
over decades -- desensitize the general public on matters of sex. A
brilliant and remarkably tenacious woman, she wrote pamphlets,
published newspapers and books, smuggled birth control devices,
founded birth control clinics and got arrested -- all to raise the
issue of birth control from the perspective of women’s rights, at
the same time publicly downplaying her own anarchist and eugenicist
leanings She succeeded in her efforts, and she and her friends were
pleasantly surprised when after the pill’s release in 1960, popular
opposition to birth control rapidly diminished.

While Sanger was primarily a political activist using the language
and methods of class warfare to foster grassroots support for her
movement, others sought to justify the need for birth control through
geopolitical arguments. Generously funded by important private
foundations, eugenicist academics like Frank Notestein and Kingsley
Davis developed demographic models that were appealing by virtue of
their simplicity and logic. They were also founded on a vision of the
human person where self-interest was the driving force of every human
action and a human being’s capacity for transcendence was a priori
disallowed.

Aided by their academic prestige and an abundance of financial
resources, they argued the need for birth control as the most
effective way of avoiding the otherwise inevitable depletion of the
earth’ resources by a growing population of consumers. Both these
groups skillfully influenced public opinion in the post-war period to
soften opposition to the pill.

Scientific obstacles

The scientific obstacles to development of the pill were
substantial as well. Most experts had settled on progesterone as the
preferred agent, but progesterone --like estrogen and most other
steroid hormones -- was digested, not absorbed, when taken by mouth.
Chemists sought to alter the structure of the naturally occurring
hormone so that it could be absorbed orally and still retain its
natural effects. Raw progesterone was very expensive because it was
very hard to come by. Until the 1940s,European pharmaceutical firms
held a virtual monopoly on steroid hormone production, but their
sources were limited to crude biological material from animal
products: glands obtained from slaughterhouses,hormone derivatives
obtained from the urine of pregnant animals. For example, the drug
"Premarin", commonly used as an estrogen supplement,is an
acronym of the terms "pregnant mare urine". These
inefficient low-yield processes were inadequate to meet the high
demand for hormones

The challenge was to discover alternate sources of steroid
molecules. This was possible because the hormones involved in human
reproduction belonged to a large group of natural chemical compounds
with a very similar structure. All the steroids have4 basic rings and
their different effects in the body depend upon the addition or
deletion of side chains to the rings.

Among those taking up the challenge was Russell Marker, a botanist
and biochemist who sought and found an important source of steroid
hormones in plants. Between 1939 and 1943,Marker and his team
demonstrated that plant compounds called"sapogenins", could
be used as precursors of steroid synthesis. He devoted himself to
identifying plants with high concentrations of sapogenins. In 1941,
while on a search for plant sources in New Mexico he stumbled on a
reference book describing a tuberous plant of the Dioscorea family: a
common yam plant called "barbasco" by the natives of
eastern Mexico (Veracruz) where it grew abundantly. He decided to
analyze Dioscorea plants, obtained samples and confirmed very high
levels of a sapogenin called diosgenin. The yam species Dioscorea
villosa was particularly suited to his work.

The Mexican connection

Marker
developed a simple,five-step method of converting diosgenin to
progesterone, a process called the "Marker degradation". He
approached Parke-Davis, an American pharmaceutical firm that had
supported his early research at Penn State, encouraging them to set
up a production center in Mexico, but they declined.

Being a pragmatic person, he sought local support by checking the
Mexico City telephone book for chemistry labs that might be willing
and able to work with steroid hormones. He found"Laboratorios
Hormona", a company founded by two eastern European emigres,
Emeric Somlo and Federico Lehmann. When they first met, Marker showed
them a sample of his work: 80 grams of pure progesterone,representing
almost one third of the world’s supply of the chemical. They agreed
to form a new company, naming it Syntex Laboratories, from"synthesis"
and "Mexico". After a year of successful work, Marker and
his partners disagreed over finances, and he left the company, taking
the instructions for synthesizing progesterone from diosgenin along
with him.

Syntex executives then hired George Rosenkranz, a Swiss-trained
Hungarian chemist who had been stranded in Havana since 1942. The
Pearl Harbor attack occurred while he was on his way to Quito,
Ecuador to found a university chemistry department there. Rosenkranz
was eventually able to piece together Marker’s process, and within
a year Syntex was once again producing progesterone from diosgenin.
By the 1970s, Syntex had become a billion dollar corporation, and one
of the world’s largest producers of steroid hormones

It should be noted that Syntex sought first to produce industrial
amounts of corticosteroids. Progesterone derivates were a secondary
priority. But when Upjohn and Pfizer in the US beat out the Eastern
Europeans from Syntex in developing efficient techniques for mass
production of cortisone, Syntex priorities shifted. The Mexican
chemist and technicians who had been assigned to the lower priority
research – synthesizing an orally absorbed version of progesterone
-- now held the key to the company’s future.

It was a young Mexican chemist, Luis Miramontes, who succeeded
under the supervision of the Austrian-born Carl Djerassi. They called
the orally-active progestational substance norethindrone. Djerassi
later claimed that they did not at that time intend to produce a
hormonal contraceptive specifically, simply a compound with
potentially marketable uses. Regardless, he has been identified and
identifies himself as the father of the birth control pill, and he
has expressed his sense of fatherhood artistically.

The American connection

Syntex
proved to be a very efficient hormone factory, but as a Mexican
company, they lacked access to the US market and so sought to develop
partnerships with established US firms. Their efforts eventually led
them to Shrewsbury,Massachusetts and the Worcester Foundation for
Experimental Biology.

Gregory Pincus was a zoologist, an authority in the reproduction
of mammals and an eccentric. He was the first to succeed at in vitro
fertilization in mammals. He used rabbits. Later in the 1930s, he
produced a rabbit by parthenogenesis, and he allowed his work to be
profiled in Collier’s magazine. In that article – the cover story
-- he was misquoted admitting his intention to attempt IVF in humans.
As a result, according to pill biographer Bernard Asbell, the public
came to view him as kind of Dr Frankenstein. He was denied tenure at
Harvard, and so became an independent consultant, founding the
Worcester Foundation for Experimental Biology in 1944.

The Worcester Foundation was intended to be a place for drug
companies to send promising chemicals to test their pharmacological
effects in animals. Their initial attempts, working primarily for GD
Searle, were disasters and the Worcester Foundation almost went out
of business several times. The change in his fortunes began in 1951
when he met Margaret Sanger at a dinner hosted by Abraham Stone, an
executive of the Planned Parenthood Federation.

Sanger had been looking for a scientist with his skills, who would
also be willing to take on a controversial project Pincus’
collaboration with Sanger and Planned Parenthood started him down the
path to the pill, but their financial support was sporadic and
limited. Real progress in identifying an orally active birth control
pill did not occur until Katherine Dexter McCormick became involved,
lending abundant financial support to the project.

McCormick was the heiress by marriage to the International
Harvester fortune. Born into a distinguished family of progressive
Chicago attorneys, she was the second woman ever to graduate from
MIT, the first with a degree in the sciences. She gave up plans to
study medicine and reluctantly married Stanley McCormick, who within
18 months had to be institutionalized for schizophrenia. They had no
children, and lived apart for most of their lives. She was an ardent
supporter of women’s suffrage and birth control, having first
crossed paths with Margaret Sanger in 1917.

After Mr. McCormick’s death in 1947, she immediately stopped
funding schizophrenia research, and shifted her attention to other
projects, in particular birth control. Historians acknowledge the
critical importance of her financial backing in accelerating the
development of the pill. Because of McCormick and a few other private
benefactors, the pill was produced using not a single dollar of
public money.

The road to the Pill

With McCormick’s close involvement and funding, Pincus was able
to ratchet up his efforts. He andd his colleague, Min Chueh Chang,
screened hundreds of hormonal products in animal models, and in the
end concluded that two –norethindrone, discovered by Miramont and
Djerassi at Syntex in 1951; and d norethinodrel, an almost identical
compound produced by Frank Colton at GD Searle two years later –
were the best candidates for human trials. Pincus found that both of
these compounds retained potent progestational effects when given
orally and were effective contraceptives in a variety of mammals.

The next step along the path to approval of the Pill would require
studying these compounds in women, and so they turned to a physician
– John Rock – who was an obstetrician-gynecologist.
Harvard-trained, a pioneer in the treatment of human infertility and
Irish-Catholic, Rock -– from the perspective of politically astute
birth control activists -- was the perfect man for the job. When he
was approached by advocates of birth control, Rock had already
devoted decades to the study of infertility and was renowned for
being the first -– along with his Harvard colleague Arthur Hertig
-– to successfully fertilize a human egg in vitro.

Pincus and Rock had known each other in the1930s. Pincus had
followed Rock’s attempts to develop methods to detect ovulation and
had provided him with chemicals for clinical testing. They had lost
touch in the 1940s, but renewed their contact during a chance meeting
at a scientific convention in 1952. At the meeting, they learned that
both were using the same compounds – estrogen and progesterone –
to achieve opposite ends: Pincus contraception infertile rabbits and
Rock conception in infertile women. Within a short time, they agreed
to collaborate to develop an oral contraceptive pill.

Clinical trials begin

In
1954, Rock began the first clinical trials under the guise of another
fertility study. This was the first-ever human trial of an oral
contraceptive. The drug Rock used was the one developed by Colton at
Searle, named norethinodrel. Rock and Pincus selected norethinodrel
because Djerassi’s version –norethindrone -- caused the
enlargement of male rat’s testicles and so it was feared that it
might have "masculinizing effects" that would hamper the
acceptance of an oral contraceptive. What they did not know was that
the Searle product they selected had been inadvertently contaminated
with a small amount of estrogen, and that likely masked the
androgenic effect of norethinodrel.

The first human trials of norethinodrel were designed to measure
ovulation rates and other effects on the reproductive system. It was
first tested in Brookline, Massachusetts,on 50 women who were
patients of Rock’s infertility clinic. None of them showed evidence
of ovulation while taking the pill. The second group tested included
23 female medical students from the University of Puerto Rico.

Within a few months of the trial, half of the women withdrew from
the study -- despite veiled threats of adverse academic repercussions
by some of the investigators -- citing side effects and cumbersome
data collection requirements. A third group --patients at the local
psychiatric hospital in Worcester – was also given norethinodrel
and provided data that eventually led to the approval of large-scale
trials to monitor its contraceptive effects specifically

The first large-scale study of norethinodrel's contraceptive
effect was conducted in Puerto Rico, a site not chosen randomly.
Comstock laws were never in force there; it was an island with very
high population density; and the local government was very
cooperative, having established a network of family planning clinics
with the assistance of Planned Parenthood years before In addition,
Pincus noted that the US press would be less likely to interfere if
studies were conducted away from the mainland. The study began in
April, 1956 under the supervision of Edris Rice-Wray, an
American-trained physician with ties to the medical school, the
public health department of Puerto Rico. She had run a family
planning clinic there, and trained health care workers in
contraceptive use. Norethinodrel proved to be a highly effective
contraceptive, despite the side effects that began to emerge.

Pincus, Rock and Searle executives were soon satisfied that the
contraceptive efficacy of norethinodrel had been adequately
demonstrated. In 1957, G.D. Searle marketed norethinodrel as Enovid
-- not for contraception but for "menstrual problems". The
package insert prominently noted as a "warning" that the
drug could induce temporary infertility as a side effect. This was in
effect Searle’s trial balloon. They quickly learned that
prescriptions for the Pill far exceeded the number of women who had
previously complained of menstrual problems.

50th anniversary

Three years later -- on May 9,1960 -- the FDA approved the Pill to
be used for birth control. This was the first product to be approved
by the FDA that was not designed to treat an illness but rather to
modify a normal process.

The half century defined by the emergence of the science of human
reproduction around 1910 and the approval of the first hormonal
contraceptive pill in 1960 was a period of dramatic scientific and
social change. Science demystified human reproduction,breaking down
the process into its basic components and making it accessible to
manipulation.

These new scientific insights offered some people – a relatively
small group of influential individuals persuaded by a materialist
worldview and eugenicist principles – an opportunity to advance
their ideology of social engineering on a global scale. They were
radical political activists working together with brilliant,ambitious
scientists and academics, and wealthy agnostics, who eventually
succeeded in presenting birth control as a moral imperative for
modern societies. An analysis of the effects of the hormonal
contraceptive on individuals and societies over the ensuing 50 years
should provide important opportunities to value the mystery of the
generation of new human life more fully.

Jose A. Bufill, MD, lives in South Bend, Indiana where he works
as a cancer specialist His articles on bioethics have appeared in the
opinion pages of major US newspapers. Some of them may be read at www.brasstack.blogspot.com

For further reading

Sexual
Chemistry is an excellent scholarly work on the history of the
Pill. A briefer history is related in On
the Pill. The
Fertility Doctor is a recent account of the tragedy of John Rock,
written by two sisters, one a historian the other a gynecologist. Birth
Control in America: The Career of Margaret Sanger steers a course
between hagiography and hostility. Katherine
Dexter McCormick: Pioneer for Women's Rightstakes a benevolent
view of its subject, but does not skate over her troubled life. Carl
Djerassi has written two entertaining books about his own role, This
Man's Pill and The
Pill, Pygmy Chimps and Degas' Horse.