Penny le Couteur & Jay Burreson (35 page)

Testosterone is an anabolic steroid, meaning that it is a steroid that promotes muscle growth. Artificial testosterones—manufactured compounds that also stimulate the growth of muscle tissue—have similar structures to testosterone. They were developed for use with injuries or diseases that cause debilitating muscle deterioration. At prescription-level doses these drugs help rehabilitate with minimal masculinizing effect, but when these synthetic steroids, like Dianabol and Stanozolol, are used at a ten or twenty times normal rate by athletes wanting to “bulk up” the side effects can be devastating.

Increased risk of liver cancer and heart disease, heightened levels of aggression, severe acne, sterility, and shriveled testicles are just a few of the dangers from the misuse of these molecules. It may seem a bit odd that a synthetic androgenic steroid, one that promotes male secondary characteristics, causes the testes to shrink, but when artificial testosterones are supplied from a source outside the body, the testes—no longer needing to function—atrophy.

Just because a molecule has a similar structure to testosterone does not necessarily mean it acts like a male hormone. Progesterone, the main pregnancy hormone, not only has a structure closer to that of testosterone and androsterone than Stanozolol but is also more like the male sex hormones than the estrogens. In progesterone a CH
₃
CO group (circled in the diagram) replaces the OH of testosterone.

This is the only variation in the chemical structure between progesterone and testosterone, but it makes a vast difference in what the molecule does. Progesterone signals the lining of the uterus to prepare for the implantation of a fertilized egg. A pregnant woman does not conceive again during her pregnancy because a continuous supply of progesterone suppresses further ovulation. This is the biological basis of chemical contraception: an outside source of progesterone, or a progesteronelike substance, is able to suppress ovulation.

There are major problems with the use of the progesterone molecule as a contraceptive. Progesterone has to be injected; its effectiveness is very much reduced when taken orally, presumably because it reacts with stomach acids or other digestive chemicals. Another problem (as we saw with the isolation of milligrams of estradiol from tons of pig ovaries) is that natural steroids occur in very minute quantities in animals. Extraction from these sources is just not practical.

The solution to these problems is the synthesis of an artificial progesterone that retains its activity when taken orally. For such a synthesis to be possible on a large scale, one needs a starting material where the four-ring steroid system, with CH
₃
groups at set positions, is already in place. In other words, synthesis of a molecule that mimics the role of progesterone requires a convenient source of large amounts of another steroid whose structure can be altered in the laboratory with the right reactions.

We have stated the chemical problem here, but it should be emphasized that we are seeing it from the perspective of hindsight. Synthesis of the first birth control pill was the result of an attempt to solve quite a different set of puzzles. The chemists involved had no idea that they would eventually produce a molecule that would promote social change, give women control over their lives, and alter traditional gender roles. Russell Marker, the American chemist whose work was crucial to the development of the pill, was no exception; the goal of his chemical experimentation was not to produce a contraceptive molecule but to find an affordable route to produce another steroid molecule—cortisone.

Marker's life was a continual conflict with tradition and authority, perhaps fittingly for the man whose chemical achievements helped identify the molecule that would also have to battle tradition and authority. He attended high school and then college against the wishes of his sharecropper father, and by 1923 he had obtained a bachelor's degree in chemistry from the University of Maryland. Although he maintained that he continued his education to “get out of farm work,” Marker's ability and interest in chemistry must also have been factors in his decision to pursue graduate degrees.

With his doctoral thesis completed and already published in the
Journal of the American Chemical Society,
Marker was told that he needed to take another course, one in physical chemistry, to fulfill the requirements for a Ph.D. Marker felt this would be a waste of valuable time that could be more profitably spent in the laboratory. Despite repeated warnings by his professors about the lack of opportunity for a career in chemical research without a doctoral degree, he left the university. Three years later he joined the research faculty of the prestigious Rockefeller Institute in Manhattan, his talents obviously having overcome the handicap of not finishing his doctorate.

There Marker became interested in steroids, particularly in developing a method to produce large enough quantities to allow chemists to experiment with ways to change the structure of the various side groups on the four steroid rings. At this time the cost of progesterone isolated from the urine of pregnant mares—over $1,000 a gram—was beyond the means of research chemists. The small amounts extracted from this source were mainly used by wealthy racehorse owners to prevent miscarriages in their valuable breeding stock.

Marker knew that steroid-containing compounds existed in a number of plants, including foxglove, lily of the valley, sarsaparilla, and oleander. Though isolating just the four-ring steroid system had not been possible so far, the quantity of these compounds found in plants was much greater than in animals. To Marker this was obviously the route to follow, but once again he was up against tradition and authority. The tradition at the Rockefeller Institute was that plant chemistry belonged in the department of pharmacology, not in Marker's department. Authority, in the person of the president of Rockefeller, forbade Marker to work on plant steroids.

Marker left the Rockefeller Institute. His next position was a fellowship at Pennsylvania State College, where he continued to work on steroids, eventually collaborating with the Parke-Davis drug company. It was from the plant world that Marker was eventually to produce the large quantities of steroids that he needed for his work. He began with roots of the sarsaparilla vine (used in flavoring root beer and similar drinks), which were known to contain compounds called
saponins,
so named because of their ability to make soapy or foamy solutions in water. Saponins are complex molecules, though nowhere near as large as polymer molecules like cellulose or lignin. Sarsasaponin, the saponin from the sarsaparilla plant, consists of three sugar units attached to a steroid ring system, which in turn is fused at the D ring to two other rings.

It was known that removing the three sugars—two glucose units and a different sugar unit called rhamnose—was simple. With acid the sugar units split off at the point indicated by the arrow in the structure above.

It was the remaining portion of the molecule, a
sapogenin,
that presented problems. To obtain the steroid ring system from sarsasapogenin, it was necessary to remove the side grouping circled in the next diagram. The prevailing chemical wisdom of the day was that this could not be done, not without destroying other parts of the steroid structure.

Marker was sure it could be done, and he was right. The process he developed produced the basic four-ring steroid system that, with only a few more steps, gave pure synthetic progesterone, chemically identical to that produced in the female body. And once the side group was removed, synthesis of many other steroidal compounds became possible. This procedure—the removal of the sapogenin side grouping from the steroid system—is still used today in the multibillion-dollar synthetic hormone industry. It is known as the “Marker degradation.”

Marker's next challenge was to find a plant that contained more of the starting material than sarsaparilla. Steroid sapogenins, derived by removing sugar units from the parent saponins, can be found in numerous plants other than the sarsaparillas, including trillium, yucca, foxglove, agave cactus, and asparagus. His search, involving hundreds of tropical and subtropical plants, eventually led to a species of
Dioscorea,
a wild yam found in the mountains of the Mexican province of Veracruz. By now it was early 1942, and the United States was involved in World War II. Mexican authorities were not issuing plant-collecting permits, and Marker was advised not to venture into the area to collect the yam. Such advice had not stopped Marker before, and he did not let it get in his way now. Traveling by local bus, he eventually reached the area where he had been told the plant grew. There he collected two bags of the black foot-long roots from
cabeza de negro
(black head), as the yams were known locally.