Luis E. Miramontes: _{Químico e inventor de anticonceptivos orales}

A senior thesis becomes a world-famous invention

Luis Ernesto Miramontes Cárdenas (hereafter, Miramontes) was born on March 16, 1925. His father, Don Candelario Miramontes Briseño, and his mother, Doña Esther Cardenas Aréchiga, were living in Tepic, in the state of Nayarit, Mexico when Miramontes was born. Other than how he appeared in a few family photographs, virtually nothing is publically known concerning Miramontes’ early life. By the time he was a teenager, however, he was enrolled at the Preparatory National School of Universidad Nacional Autónoma de México (UNAM). He remained at UNAM for his undergraduate work in chemistry and chemical engineering from 1945 to 1949. In 1948, he began graduate courses although he was still required to complete an undergraduate thesis project. The opportunity to do such a thesis became available in 1950 and not in the usual way.

Rather than being matched with a professor in his own department, an emerging Mexico City chemical company called Syntex actually recruited Miramontes to do his thesis projects in one of their own labs. Despite his youth and student status, Miramontes demonstrated unusual talent in chemical laboratory techniques. Syntex recognized this, and the recruitment to do his thesis at the company was also recruitment for a job. Initially, he did not know precisely what he would be working on, but he knew that the company focused on synthesizing hormones. He also knew that he would be working with two seasoned chemists: Carl Djerassi and George Rosenkranz. It sounded like an unprecedented opportunity for a student who had yet to complete an undergraduate degree, so he accepted the offer.

As a new researcher at Syntex, the 25 year-old Miramontes began working with Djerassi and Rosenkranz on a project to develop a synthetic form of the female hormone progesterone. Already by that time, progesterone was being used as a contraceptive, but Djerassi and Rosenkranz wanted to make it work better, and Mexico was the place to do it. Today, nearly all hormones used in medicine are produced with genetic engineering of microorganisms, which can be done in any part of the world. In the 1950s, however, scientists knew that the only way to make synthetic progesterone would be to alter natural progesterone through some kind of elaborate chemical process. To do that would require natural progesterone as a starting material, what chemists call a substrate. The easiest and cheapest way to get progesterone at the time was from a Mexican breed of yam, and this is why biochemical hormone researchers, including Djerassi and Rosenkranz, were gravitating to Mexico.

Creating a synthetic kind of progesterone was an ambitious goal because it required numerous steps in chemical synthesis. One section of progesterone, a complex organic molecule, had to be altered in a certain way (certain atoms had to be moved around, or replaced with atoms of other chemical elements), then that chemical product itself had to be altered, then altered again, and again to make a new molecule with the desired chemical properties.

On October 15, 1951, under the direction of Djerassi and Rosenkranz, Miramontes worked out the final step in the process to create a synthetic progestin (a progesterone-like hormone). The synthetic progestin was called 19-nor-17α- ethinyl testosterone – or “norethindrone” for short (Figure 2). The expected application of norethindrone was contraception to replace natural progesterone. Experiments with laboratory animals and then humans showed norethindrone to be eight times more potent than natural progesterone, and that was not the only advantage. Unlike natural progesterone, which had to be injected, norethindrone retained its potency when taken orally. This meant that hormonal contraception could be made much more convenient and attractive to women.

For that to happen, of course, norethindrone would have to be approved by government health agencies around the globe, but that would happen in time. Soon, norethindrone became a prime component of the first oral contraceptive pills, and even today it is used in many contraceptive formulations. Synthesis of norethindrone depended heavily on the segments of the chemical process that Miramontes conducted. Consequently, the thesis project earned the student his undergraduate degree, and five years later something else: a US patent. On May 1, 1956, Miramontes was named along with the two senior chemists on US patent 2,744,122 for “oral contraceptives.”

A chemical renaissance man working for the environment

Despite being wrapped up with refining the norethindrone synthesis technique and writing numerous scientific papers about it in the early 1950s, Miramontes did not allow the decade to go by without completing graduate studies at UNAM. He completed his doctoral research primarily in 1954-1956, although he had begun it in 1948, overlapping with the end of his undergraduate studies. Given his work at Syntex, he was a graduate student with an unusual amount of experience in synthetic chemistry, and after obtaining his doctorate he was appointed to the faculty. Around this time, he joined other researchers to found UNAM’s Institute of Chemistry.

He also continued to work in industry and involved himself in a diversity of chemical topics, from pharmaceuticals to organic chemistry, chemistry of the atmosphere, and petrochemistry. Research in the latter field eventually led him to become Deputy Director of Research of the Mexican Institute of Petroleum. Additionally, his research in petroleum chemistry and atmospheric chemistry started to dovetail in the early 1970s in connection with automobile technology. This was an era when Americans were changing how they thought about cars.

For most of the 20th century, the science revolving around engines and gasoline was completely focused on bolstering performance, giving consumers more power and speed. With only a few exceptions, people were not concerned about what this was doing to the air. In 1965, however, Clair Patterson, a Cal Tech geochemist famous for using lead in special crystals from a meteorite to determine the precise age of the Earth, published a bombshell: Lead from gasoline was accumulating in the environment rapidly at extremely dangerous levels. The source of gasoline lead was a chemical called tetraethyl lead that was added to the fuel as an “anti-knock” agent. For the first time, chemists and engineers working in, and in connection with, the auto industry were thinking about how to improve efficiency and remove toxins from car exhaust.

Given his involvement in both petrochemistry and atmospheric research, Miramontes naturally gravitated to the realm of car exhaust engineering. Prohibitions against leaded gasoline would not come to fruition until the 1980s, but in the years following Patterson’s discovery, chemists like Miramontes were thinking of how they might make leaded gasoline safer by removing lead and other toxins in car exhaust systems (see Figure 3 for information on the relationship between lead levels in gasoline and in humans). Lists of patents in the early 1970s show that researchers were approaching the problem from both mechanical and chemical perspectives. Miramontes’ perspective, of course, was chemistry, so he developed a chemical process for converting the exhaust gases into harmless products. For this, he filed a patent in 1972 (published 1974).

Leaded gasoline was eventually banned in the United States and by the early 2000s in nearly all other countries. Phase-out has taken many years across the planet, but as of 2015 leaded remained legal only in Yemen, Myanmar, Afghanistan, and North Korea, and with little or any actually being sold in the latter two countries. In the course of that time, catalytic converters came into use to improve engine efficiency, but the earliest catalytic converters could not operate with leaded gas. Thus, Miramontes sought to develop a new chemical process enabling a catalytic converter that could function with leaded gas. He developed one using ceramic with gamma alumina, impregnated with chromium, copper, and nickel. This earned him yet another patent in 1996.

The pill goes on the market

While Miramontes was becoming a kind of Renaissance man in the various fields of chemistry, things were happening with norethindrone and the contraceptive pill that it made possible. In 1962 the United States Food and Drug Administration (FDA) approved norethindrone for contraceptive use. Within two years, the hormone could boost the major share of the birth control pill market in the US. It was at that time that US Department of Patents named the contraceptive pill as one of the 40 most important inventions since the year 1794.

The reason why norethindrone and the researchers who created it enjoyed such recognition so quickly after FDA approval has a lot to do with the fact that it was part of an “oral contraceptive.” When Miramontes went to work for Syntex, the use of hormones for contraception was not new. As noted earlier, however, the hormones had to be injected. The novelty of norethindrone was that it, and another class of female hormones called estrogens, could be taken in oral form. That was a lot more convenient than having contraceptive hormones administered at the doctor’s office. Much better, the pill could go home with each patient, it was small and easy to use, and, importantly, if used correctly, the effectiveness proved to be almost 100 percent (Figure 4).

As his career progressed throughout multiple areas of medicine, Miramontes continued to refine and reshape variations on norethindrone, as well as other clinically useful hormones. By the early 1970s, this earned him more than a dozen patents, and from the 1980s until his death in 2004 and beyond he has been recognized with various awards for contributions to humanity. For instance, in 1985 he was granted the "Estado de México" medal for sciences and arts. That same year, he also was honored by the government of the state of Nayarit (his birth state) and recognized academically by Technological Institute of Tepic (his birth city). A year later, he was awarded Mexico’s National Prize in Chemistry. In 1992, a hospital in Tepic was renamed as "Luis Ernesto Miramontes Cardenas Hospital," and in 1994 he won Nayarit’s "Amado Nervo" Medal.

At the turn of the 21st century, a group Nobel Laureates named oral contraceptives as one of the most important inventions of the last 2,000 years. Soon after that, on the 50th anniversary of norethindrone, Miramontes and Rosenkranz were given tributes by UNAM and Mexico’s Ministry of Health (Figure 5). In 2004, a committee of the United Kingdom’s Engineering and Technology Board chose Miramontes’ norethindrone as the 20th most important invention of all time. A year later, the Mexican Academy of Sciences called the hormone the number one contribution to science.

The list of honors goes on, though probably Miramontes will be remembered best for norethindrone, which today has a variety of medical uses. In contraceptive applications, it is used in what is commonly called the “mini-pill,” meaning an oral contraceptive that does not contain estrogen (this is in contrast to standard birth control pills which today use estrogen-like agents in combination with progestins other than norethindrone). From the 1970s through the 1990s, norethindrone was put into use for clinical applications beyond contraception. Thus, today it is given for endometrial hyperplasia, endometriosis, excessive menstrual bleeding, hypogonadism (inadequate ovaries), and acne.

Millions of women around the world have benefited from this one synthetic hormone. Considering this, together with Miramontes’ work on atmospheric chemistry and detoxification of engine exhaust, it should be no surprise that scientists, historians, and other thinkers representing multiple fields have come to a similar conclusion: Miramontes has been one of science’s greatest. Certainly, without his research, the last few decades would have been immeasurably different, and millions have Miramontes to thank for his contributions to human health.