Pioneering Studies of the “Morning-After” Pill

Abstract

Yale School of Medicine produced the first proof-of-concept study on the viability of a “morning-after” pill for human use. This study was a result of a fruitful collaboration between a pair of Yale scientists, Drs. John M. Morris and Gertrude van Wagenen, who sought a non-abortion, post-coital contraceptive. They tested a variety of hormones, hormone-based synthetic drugs, and other compounds in monkeys in an effort to uncover a compound that was non-toxic but highly effective. Unfortunately, although they were unable to identify such a drug, their initial studies inspired other scientists to further pursue the concept of a “morning-after” pill, leading to the development of Food and Drug Administration (FDA)-approved emergency contraceptives.

In 1966, two Yale School of Medicine researchers published a small study that showed for the first time that certain estrogenic compounds can prevent pregnancy if taken within a few days after sexual intercourse [1,2]. This was the first instance of a compound successfully used as a “morning-after” pill. The authors of this study, John McLean Morris, MD, and Gertrude van Wagenen, PhD, both members of the Department of Obstetrics and Gynecology, undertook a collaboration that generated six peer-reviewed publications that explored the use of various compounds as emergency contraception. Dr. van Wagenen’s expertise in using rhesus macaque monkeys, Macaca mulatta, as a model system and Dr. Morris’ interest in developing new contraceptive methods set the stage for these pioneering studies. Yale School of Medicine was an ideal place for these types of investigations because it housed a successful breeding population of macaque monkeys and possessed well-documented records on their fertility over a long period.

When these studies were undertaken, it was already known that estrogenic compounds at a sufficient dosage prevent ovum implantation in some non-primate mammalian animals, such as rabbits [1]. It was also well-known that an optimum balance of estrogen and progesterone is needed to promote implantation, implying that changing the ratios of different hormones can influence the probability of implantation [3]. However, the estrogenic compounds used in these early studies were not examined for toxicity in humans, making these drugs unusable in a clinical setting. Morris and van Wagenen made use of the fact that the reproductive system in Macaca mulatta is very similar to that of humans. More specifically, female rhesus macaque monkeys are known to have a comparable menstrual cycle, dependent on changes in hormonal levels, to human females, making them an ideal model system to test estrogenic candidates.

In their first study, Morris and van Wagenen tested several known estrogens and a novel compound, ORF-3858, developed by the Ortho Research Foundation in New Jersey. This new compound was previously shown to be 100 percent effective in preventing ovum implantation in rabbits. Another distinction was that this compound was non-toxic and non-teratogenic, meaning that it did not impair the growth of an already implanted embryo, even when given at doses that did not prevent implantation. In monkeys, this compound also proved to be a 100 percent effective when given orally for 6 days after mating.

Since further characterization of ORF-3858 showed that this molecule had estrogenic properties, established estrogens were re-evaluated for their anti-implantation properties. Morris and van Wagenen had shown that diethylstilbestrol, ethinyl estradiol, and mestranol prevented implantation in rabbits very efficiently [1]. These same compounds were ineffective in preventing implantation in monkeys at the same dosage, but when the concentration was increased and treatment given orally or by intramuscular injection for 6 days, they were able to prevent ovum implantation. This set the stage for a preliminary clinical trial that showed that 50 mg of diethylstilbestrol or 0.5 mg of ethinyl estradiol for 4 to 6 days after coitus was effective in preventing pregnancy. Though this study was not statistically significant, it represented the first time that prevention of implantation was demonstrated in humans [2].

Unfortunately, diethylstilbestrol and ethinyl estradiol have several side effects, such as nausea and breast soreness, which are common to estrogenic compounds. An ideal post-coital contraceptive would be non-toxic, non-teratogenic, highly effective against implantation of the ovum, and exhibit few side effects. In an effort to find such compounds, Morris and van Wagenen turned to alkaloids and antimetabolites to possibly identify a drug that would be effective yet induce few negative effects. They tested several compounds previously indicated to have an effect in rodents, rabbits, and monkeys. They found that some molecules such as colcemide were very effective in preventing a full-term pregnancy but did so by being extremely toxic to the developing fetus, not by preventing implantation. This drug also proved to be extremely toxic, particularly because the effective dosage was very close to the toxic dosage [3]. Moreover, colcemide was ineffective at preventing pregnancy in primates. They found that these compounds did not produce the same effect in rabbits and primates and the method of delivery (oral or intra-peritoneal injection) of the drug seemed to change its efficacy [3].

In light of these issues with non-estrogenic compounds, the Morris and van Wagenen team turned back to examining the use of synthetic estrogens and antiestrogens to prevent the implantation of the ovum. Synthetic estrogens were especially of interest because they had been shown to act as competitive inhibitors of estrogen while being poorly estrogenic themselves. When several such compounds were tested in rabbits and monkeys, a few, such as clomiphene, showed low effectiveness and produced severe side effects, such as prolonged amenorrhea [4]. ORF-3858 was the only compound that showed high effectiveness in preventing pregnancy in monkeys at a dose of 2 mg/kg for 6 days after mating and did not affect ovulation or the menstrual cycle [4].

This novel compound showed promise in being used as an anti-implantation drug, but its mechanism of action was still unknown. To study this more extensively, the uterine tissue of both untreated and treated animals was examined. With ORF-3858, the endometrium seemed to undergo degeneration, but the fetus and fetal membranes were intact [4]. Treatment with other compounds, such as clomiphene, seemed to directly affect the blastocyst. To test if the effect was exerted on the endometrium or on the blastocyst, Morris and van Wagenen performed a blastocyst transfer experiment by extracting blastocysts from either a treated or untreated uterus, transferring it to another uterus, and measuring the rate at which implantation occurred. There was no significant difference between the implantation of blastocysts in the control and treatment groups, showing that the blastocyst itself was unaffected by drug treatment [4].

To better understand what effect these estrogenic compounds were having, Morris, van Wagenen, and colleagues took blood samples from untreated and treated post-ovulation monkeys and analyzed these samples’ prostaglandin and progesterone levels. Progesterone levels dropped rapidly after treatment, while prostaglandin levels rose at the same time [5]. Unfortunately, this was not enough to establish a causal relationship between the changes in these hormones and the anti-implantation properties exhibited by the estrogenic compounds tested.

Morris and van Wagenen were in search of a molecule that prevented implantation, for which they adopted the term “interceptives” [6]. These were different from abortifacients, since implantation would not have occurred. In 1977, Yupze and Lance developed an emergency contraception regimen for humans of 0.1 mg ethinylestradiol and 0.5 mg levonorgestrel [7], and this combination regimen was in place as a emergency contraception method until it was replaced recently with a levonorgestrel-alone treatment marketed as Plan B [8]. Though the mechanism of action of levonorgestrel is still unknown, it has been shown to not to be an “interceptive” [8]. Thus, although Morris and van Wagenen’s goal was not achieved, their initial studies of the effects of estrogenic compounds on ovum implantation in monkeys, based on the idea that disturbing hormonal balance can prevent implantation, paved the way for the discovery of the post-coital emergency contraceptives approved by the FDA for human use today.

Abbreviations

FDA

Food and Drug Administration