The "Marker Degradation"

The decade of The Sex Hormones

The Decade of the Sex Hormones -- that's how steroid chemists often refer to the 1930s, when the molecular structures of the male hormone, testosterone, the female hormones, estrone and estradiol, and the pregnancy hormone, progesterone, were determined and first introduced to medical practice as drugs. Much attention was focused on progesterone because of its value in treating various menstrual disorders and preventing certain types of miscarriages; however, its high cost severely restricted its use. The cost of progesterone and other important steroids* fell drastically in the 1940s with the creation of the Mexican steroid industry. According to Carl Djerassi ("The Father of the Pill"), the "Mexican connection stemmed from the work of one gutsy individualist, Russell E. Marker," about whom more stories have been told, "many of them apocryphal… than about almost any other chemist."

In 1938, Marker, then a chemistry professor at The Pennsylvania State College (now, University), proposed a remarkable new molecular structure for sarsasapogenin, a plant steroid isolated from sarsaparilla. In Marker's structure, the side chain part of the molecule (the red part of the formula below) is chemically reactive because two oxygens are connected to the same carbon atom. Earlier workers had supposedly confirmed "beyond any doubt" a sarsasapogenin structure in which the side chain was chemically inert. Using this reactivity to advantage, Marker invented a chemical reaction sequence that removed most of the atoms in the side chain. What remained duplicated the side chain of progesterone. (Chemists call such processes "degradations.") Subsequent chemical modification of the steroid ring system then yielded progesterone itself.

Diagram

Because of the high cost of sarsasapogenin and the major expense involved in these final manipulations, Marker began a search for a plant steroid of the sapogenin class with a ring structure more like progesterone. He found it in Beth root, a plant of the lily family, which already was being used in a patent medicine called "Lydia Pinkham's Compound." Japanese chemists previously had isolated this steroid from a yam of the Dioscorea family and named it diosgenin. As anticipated, when diosgenin was subjected to the "Marker Degradation," progesterone was obtained. However, neither Beth root nor the Japanese Dioscorea was an economical source of diosgenin.

In his search for a better diosgenin source, Marker recruited several botanists and launched extensive plant-collection trips mainly in the southwestern United States. More than 400 species were examined and a dozen new sapogenins were identified and characterized. Then, in November 1941, while in Texas, Marker was paging through a botany text when he saw the picture of a Dioscorea that grew in the Mexican state of Veracruz near Orizaba. The root of this plant, called cabeza de negro by the natives, was said to weigh up to 100 kilos.

* Steroids are fat-soluble compounds with complex molecular structures that occur in almost all living organisms. They always have a ring system of carbon atoms with three 6-membered rings and one 5-membered ring connected to each other. The 5-membered ring can be attached to a side chain of carbon atoms that may be quite long (e.g., cholesterol and diosgenin), short (e.g., progesterone), or even nonexistent (e.g., testosterone, estrone, and estradiol).

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