File photo: Before the circular dials and rectangular packs gained a regular spot on bathroom sinks and at the bottom of purses, the people behind them first had to prove they were effective.

The message wasn't subtle in one of the first advertisements for the birth control pill. Greek mythological figure Andromeda is shown looking upward, her wrists bound in manacles. An accompanying caption ends with a four-word promise: "freed from her chains."

On May 9, 1960, when the pill was first approved by the FDA as a contraceptive method in the US, the demand was immediate. Within four years, more than four million women had used what was then marketed under the name Enovid. Now, more a half century later, the pill is the most common birth control method used by women of reproductive age. In recent years, a social media campaign has even formed around the hashtag #ThxBirthControl.

But before the circular dials and rectangular packs gained a regular spot on bathroom sinks and at the bottom of purses, the people behind them first had to prove they were effective – and to do that, they needed to test them on humans.

Where they chose to conduct those tests marks one the most controversial – and rarely discussed – chapters in the history of a drug that symbolizes women's liberation.

In the mid-1950s, the first large-scale human trial of the pill was launched in a public housing project in Puerto Rico – and the distrust was immediate.

"The controversy over the field trials began almost the minute the first woman swallowed a pill," wrote Margaret Marsh and her sister Wanda Ronner in a biography of one the pill's creators, John Rock, a gynecologist renowned for his work on infertility. "Within weeks of the trial's start, El Imparcial, a popular newspaper, accused the project's sponsors of conducting a 'neomalthusian campaign,' and local doctors told their patients that the pill was dangerous."

When one of the researchers, Dr. Manuel Paniagua, appeared on television, the interviewer was blunt.

"Around here they say that these pills have been used only in animals in the United States and only here have they been given to women? Is this so?"

"Completely false," said Paniagua.

The truth was that little was known about the drug's effects when Rock and biologist Gregory Pincus – with the backing of birth control advocate Margaret Sanger and philanthropist Katherine McCormick – decided to launch the human trials. The drug had been tested on rats and rabbits, and on a small sampling of women in Rock's medical practice in Massachusetts. But its largest test would be in Puerto Rico, where as many as 1 500 women took the drug over several years.

Three women in the trials died. But no autopsies were conducted, and so it remains unclear if their deaths were linked to the drug, which was given in much higher doses than it is today.

Critics have compared the Puerto Rican trials to the Tuskegee Syphilis Study, in which the government conducted research on African American men in Alabama for 40 years. In 2010, the government also apologized for a US-funded study that involved deliberately infecting hundreds of Guatemalans with syphilis and other sexually transmitted diseases between 1946 to 1949.

But Marsh and other historians say the ethical questions raised by the pill's testing are more complicated than those cases.

"In some ways, it was exploitative – you're giving this drug that you don't really know for sure what its effects are going to be," Marsh said. "On the other hand, the people involved in developing it really believed it was safe."

They also believed it would give women choices, she said. Descriptions of the women in the study show that even if they were poor, and, in some cases illiterate, they were eager to have control over their family planning.

One woman, described in Marsh's book as Senora J. G. was 30 years old and had 10 children, ages 10 month to 16 years old. She also had a husband who "drank heavily and insisted on daily intercourse but claimed to be too ill to work." Another woman had five children and a husband who was hospitalized frequently for mental illness.

"Most of these women really did understand why they were taking the pill," Marsh said. "They may have been poor, but they certainly had aspirations for their families."

Before the pill, the main option women in Puerto Rico had for preventing pregnancy was sterilization, called simply "la operacion."

The theories as to why Puerto Rico was chosen as a testing ground, despite its heavily Catholic population, are multiple: It was an easy flight from the US mainland. There were no laws there against birth control. And the location's overcrowding and poverty made it especially attractive to biologist Gregory Pincus, who was concerned about global population control.

"The control of the population explosion now upon us by the limitations of births is particularly demanding in countries where the birth-rate pressure curtails already limited economic development," Pincus wrote in an article that appeared in The Washington Post on Aug 2, 1959. "Accordingly, there has been an increasing demand for a simple, easily practiced, generally acceptable, inexpensive means of contraception. Generally this demand has been for some easy medication, since the taking of medicine is a world-wide, accepted practice. 'Give us a pill' expresses the sentiment of interested social workers, nurses, public health servants."

He details how in the first year of the trial, about 25 percent of the women quit "because they either lost interest or found the medication undesirable." Dizziness and nausea were frequent complaints of the drug, which at that time was given at a much higher dose than available today. After a year in San Juan, he writes that other projects were launched in Humacao, Puerto Rico, and in Port-au-Prince, Haiti.

Pincus boasted about the drug's effectiveness in those trials – just "one doubtful pregnancy" among women who didn't miss a dose – but also complained about the lack of funding for the research.

"One of the handicaps to rapid advance in this field has been the very meager resources for research," he wrote. "The dollars available for this type of work may be counted in the thousands. . . . Because of religious doctrines and sexual taboos, birth control has been looked on askance. The scientific study of reproductive processes should command the same respect as the scientific study of disease processes. Probably the world's single most biological problem is fertility control."

When Pincus wrote the article, Enovid was already being marketed in the US as a treatment for gynecological disorders. A year later, the FDA would allow it to carry a contraceptive claim and shortly after that, concerns began spreading about the drug's safety. By August 1962, the FDA was informed that 26 women had reportedly suffered blood clots, including six who died.

FDA historian Suzanne Junod said no one, including the drug's creators, anticipated the blood clots and only later was it determined that some women are predisposed to them.

Pincus, she said, believed so strongly in the pill's safety that he sent them to female relatives.

"The experiments were both good and bad," Delia Maestre told the Orlando Sentinel, crying. "Why didn't they let us make some decisions for ourselves? I have difficulty explaining that time to my own grown children. I have very mixed feelings about the entire thing."