The Marker Degradation: Turning Plant Sapogenins into Progesterone

Between 1938 and 1940, in a laboratory at Pennsylvania State College, the American chemist Russell Marker (1902–1995) worked out a short chemical route that turned soap-like substances from plant roots into progesterone, one of the body’s key sex hormones. Until then progesterone had been made in tiny amounts from animal sources at enormous cost. Marker’s route, now called the Marker degradation, started instead from sapogenins — steroid compounds that plants such as sarsaparilla, beth root and wild yams make naturally. It is one of the clearest examples in the history of medicine of a drug supply moving from the animal body to the plant kingdom.

This page explains the chemistry in plain language: what a steroid is, why progesterone was so scarce in the 1930s, what Marker saw in the structure of a sarsaparilla sapogenin that others had missed, and how a single hot step with acetic anhydride let him cut a plant molecule down to a hormone. It then follows the route from sarsasapogenin to diosgenin and beth root, to testosterone, to Marker’s decision to patent nothing, and to the long 1947 paper that gathered the work together. The story of how Marker found his raw material in the Mexican forest, and what the industry built on it went on to make, is told on the wing’s other pages.

Table of Contents

  1. What a Steroid Is
  2. The Decade of the Sex Hormones
  3. Progesterone from Cholesterol and Urine
  4. Sapogenins: Soap-Like Steroids in Plants
  5. A New Structure for Sarsasapogenin
  6. Breaking the Side Chain: How the Degradation Works
  7. Diosgenin from Japan and Beth Root
  8. Testosterone and Other Hormones from Plants
  9. No Patents: An Open Process
  10. The 1947 Summary Paper
  11. Key Research Papers
  12. Connections

1. What a Steroid Is

A steroid is a molecule built on one particular carbon framework: four rings of carbon atoms fused side by side, three with six corners and one with five. Chemists label the rings A, B, C and D and number the carbon atoms around them, so that a change “at carbon 17” or “at carbon 11” always means the same spot. The framework itself is rigid and almost flat. What makes one steroid different from another is what hangs off it: a few oxygen atoms here and there, a double bond in one ring or another, and above all the side chain attached to the five-sided D ring at carbon 17.

That small difference in decoration is the difference between very different substances. Cholesterol, the waxy sterol found in every animal cell membrane, carries a long, branched side chain of eight carbon atoms. Progesterone, the hormone that prepares the lining of the womb and sustains early pregnancy, has exactly the same four-ring framework but only a short two-carbon side chain ending in a ketone group, plus a ketone on ring A. Testosterone has no side chain at all, only an oxygen-bearing group at carbon 17. The plant sapogenins Marker worked with have the same framework too, but their side chain is folded back into two extra rings that contain oxygen.

Seen this way, making a hormone from a natural sterol is a problem of trimming. The ring system is already there, built by a living organism; the chemist’s task is to cut the side chain down to the right length and adjust a few oxygens and double bonds. In the 1930s the difficulty was that a long hydrocarbon side chain like cholesterol’s gives a chemist almost nothing to grip. Breaking it at the right place was possible, but wasteful, and the yields were tiny. Marker’s achievement was to find natural steroids whose side chain was built in a way that could be cut cleanly.

Why the plant matters

Building a steroid from scratch in the laboratory was far beyond the chemistry of the 1930s. Every practical route to a steroid hormone therefore began with a steroid some living thing had already made — cholesterol from wool fat or brain tissue, bile acids from oxen, hormones concentrated from urine. What Marker added was a plant starting material, available in quantity from roots. Modern work has shown that plants make diosgenin from cholesterol itself, using pairs of cytochrome P450 enzymes that build the folded, oxygen-containing side chain, and that this ability arose separately in a monocot and in fenugreek (Christ et al., 2019). Those authors call diosgenin “the single most important precursor for the world steroid hormone industry”.

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2. The Decade of the Sex Hormones

The 1930s are sometimes called “the decade of the sex hormones”. In a few years European laboratories isolated and worked out the structures of estrone and estradiol, the main estrogens; testosterone, the main male hormone; and progesterone, the hormone of the corpus luteum, the small gland that forms in the ovary after ovulation. For the first time physicians could name the substances behind the menstrual cycle and early pregnancy, and chemists could draw them on paper.

Drawing a molecule and having enough of it to use were very different things. According to the American Chemical Society’s 1999 landmark booklet on Marker’s work, progesterone was valued in medicine of the time for menstrual disorders and some kinds of miscarriage, but it was scarce and very expensive. The hormone exists in the body only in tiny amounts, and the early methods of making it started from animal materials that had to be collected and processed by the ton. In his 1987 oral-history interview Marker recalled a price of about $1,000 per gram; that figure is his own recollection, but every source agrees that the hormone was a costly rarity.

The pharmaceutical industry therefore had a strong reason to look for a cheaper starting point. Whoever could make progesterone from an abundant natural raw material would change the price of the hormone, and with it the price of every compound that could later be made from progesterone. That was the problem Marker set himself when he left the Rockefeller Institute for Penn State in 1934, with his fellowship and research funded by the drug firm Parke-Davis.

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3. Progesterone from Cholesterol and Urine

Marker began where the existing methods stood. In his oral history he described first repeating the German route that started from cholesterol: about a kilogram of cholesterol went in, and the yield of hormone at the end was under one per cent. The long cholesterol side chain had to be broken by harsh oxidation, which attacked the rest of the molecule too, so most of the costly starting material was simply lost.

A second animal route went through pregnanediol, an inactive breakdown product of progesterone that the body excretes in urine. Pregnanediol already has the steroid framework and a two-carbon side chain, so turning it back into progesterone is a matter of adjusting oxygens rather than cutting carbon. Working from pregnanediol isolated from urine supplied by Parke-Davis, Marker made about 35 grams of progesterone. The ACS booklet, the Science History Institute and Marker himself all describe this as the largest single lot of progesterone made up to that time. (The sources disagree on whose urine it was — pregnant cows and mares, bulls, or human pregnancy urine — so this page leaves the animal unnamed.)

Thirty-five grams was a record, but it also showed the limits of the animal route: enormous volumes of raw material for a small amount of hormone. Marker had already decided, before leaving New York, that the better source lay in plants. His interest was in a family of plant steroids that had been known for decades but that the leading chemists of the day regarded as a dead end.

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4. Sapogenins: Soap-Like Steroids in Plants

Many plants contain saponins, substances named from the Latin sapo, “soap”, because they foam when shaken with water. A saponin is a two-part molecule: a sugar chain joined to a non-sugar core. When the sugars are split off, usually by boiling with acid, the core that remains is called a sapogenin. In one large group of plants that core is a steroid, with the same four-ring framework as cholesterol and the sex hormones.

Marker’s first plant sapogenin was sarsasapogenin, from the root of sarsaparilla (Smilax), long used in tonics and soft drinks. Others he studied came from beth root (Trillium, a plant of the lily family whose root was already used in a popular patent medicine), and from yams (Dioscorea), whose sapogenin diosgenin would become the centre of the story. Over the following years he, his students and collaborating botanists examined more than 400 plant species, mainly in the south-western United States, and described about a dozen new sapogenins; that search is told on the Mexican wild yams page.

The attraction was obvious: plant roots can be gathered by the ton, and a sapogenin already carries the full steroid ring system. The difficulty was the side chain. Every steroid sapogenin carries, attached at carbon 17, a bulky arrangement of carbon and oxygen atoms folded into two extra rings, usually labelled E and F. Earlier chemists had worked on these compounds for years and concluded that this part of the molecule could not be usefully broken down. At the Rockefeller Institute, Marker’s former colleague Walter A. Jacobs had concluded that sarsasapogenin could not be turned into a hormone intermediate — one of the reasons the Institute declined to let Marker pursue the idea there.

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5. A New Structure for Sarsasapogenin

The accepted picture of the sarsasapogenin side chain, put forward by the German chemists Tschesche and Hagedorn and accepted by Louis Fieser and others in the United States, treated it as chemically inert — a tightly closed, unreactive structure with no weak point a chemist could exploit. If that was right, sapogenins were curiosities, not raw materials.

In 1939 Marker and his co-worker E. Rohrmann published a different structure in the Journal of the American Chemical Society (Marker and Rohrmann, 1939, “The Structure of the Side Chain of Sarsasapogenin”). In Marker’s structure the side chain is a spiroketal: the two extra rings meet at a single carbon atom, and that carbon is bonded to two oxygen atoms, one from each ring. A carbon holding two oxygens in this way is a ketal, the kind of group organic chemists know can be opened under the right conditions. In plain terms, Marker argued that the side chain was not a sealed lump but a folded chain held shut by a clasp — and that a clasp can be undone.

The dispute over publication

The structure ran against the views of senior chemists. In his 1987 interview Marker described how Louis Fieser of Harvard, who refereed his papers for the journal, objected to the side-chain paper, and how the editor, Arthur Lamb, published it anyway. This is Marker’s own later account of a disagreement between two scientists who are both long dead; it is reported here as his recollection, and the published record shows only that the paper appeared. What is not in dispute is that the spiroketal structure is the one found in chemistry textbooks today, and that it was the key to everything that followed.

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6. Breaking the Side Chain: How the Degradation Works

Once the side chain was understood as a spiroketal, Marker could look for a way to open it. The step he found was simple to describe and demanding to carry out: the sapogenin was heated with acetic anhydride (the same reagent used to make aspirin from salicylic acid) at about 200 °C. Under those conditions the spiroketal clasp opens. One of the two side-chain rings is broken, and the oxygen atoms that had held it shut end up on the molecule in a form a chemist can work with.

The opened compound was then treated in an oxidation step, which split the side chain at the point where the ring had opened, and a hydrolysis step removed the fragment. What was left at carbon 17 was a short two-carbon chain. In the words of the ACS landmark booklet, “What remained duplicated the side chain of progesterone.” Marker described the general method in 1940 as the conversion of the sapogenins to the pregnenolones (Marker, 1940), the family of compounds that sits one or two routine steps away from progesterone. A short series of standard reactions — adjusting a double bond and turning an alcohol group on ring A into a ketone — then gave progesterone itself.

The sequence in outline

The first demonstration came in December 1939, when Marker and Rohrmann reported the conversion of sarsasapogenin to pregnanediol (Marker and Rohrmann, 1939, “Conversion of Sarsasapogenin to Pregnanediol-3(α),20(α)”). Pregnanediol was the very compound Marker had been turning into progesterone from urine. A plant root could now stand in for the animal source.

Why it mattered

The route was short, and it left the expensive part of the molecule — the ring framework built by the plant — untouched. Compared with the harsh cholesterol oxidation, where most of the material was lost, the sapogenin route used a large share of what went in. That is what turned a laboratory curiosity into the basis of an industry. In his 1987 interview Marker said that the degradation was still in use in Mexico at that time.

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7. Diosgenin from Japan and Beth Root

Sarsasapogenin proved the principle, but it was not the best raw material. Its rings carry no double bond, so the product of the degradation belongs to the pregnanediol series, which needs extra steps to reach progesterone. A more useful sapogenin already had a double bond in ring B, in the same place as in cholesterol, which brings the product much closer to progesterone. That sapogenin was diosgenin.

Diosgenin had been discovered in Japan. The chemists Takeo Tsukamoto, Yosio Ueno and their colleagues studied the glycosides of the Japanese yam Dioscorea tokoro in the mid-1930s, isolated the sapogenin and named it after the genus (Tsukamoto and Ueno, 1936). According to the ACS booklet and Marker’s oral history, Marker received a crude sample, purified it and took it through his degradation to progesterone. His 1940 paper on diosgenin’s chemistry carries Tsukamoto’s name as a co-author (Marker, Tsukamoto and Turner, 1940).

Trillin from beth root

Diosgenin also turned up in an American plant. Beth root (Trillium), a woodland plant of the lily family, contains diosgenin bound to sugar as the glycoside trillin. In 1940 Marker and his co-worker J. Krueger prepared trillin and converted it to progesterone (Marker and Krueger, 1940). The beth root came from North Carolina. It worked chemically, but according to Marker its roots were too small to collect in the quantities an industry would need, and the same was true of the Japanese yam. The search for a large, diosgenin-rich root is what took Marker to Mexico in 1941 and 1942 — a story told on the cabeza de negro and barbasco page.

The chemistry, in other words, was finished before the raw material was found. By the end of 1940 Marker had shown that sarsasapogenin, diosgenin and trillin could all be degraded to hormones; what remained was to find a plant that made diosgenin by the ton.

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8. Testosterone and Other Hormones from Plants

Progesterone was not the only target. Once the side chain could be opened and shortened, other hormones lay within reach. In a 1940 paper Marker reported the preparation of testosterone and related compounds from sarsasapogenin and diosgenin (Marker, 1940, “The Preparation of Testosterone and Related Compounds from Sarsasapogenin and Diosgenin”). Testosterone has no side chain at all at carbon 17, so the route goes further: the two-carbon chain left by the degradation is removed in turn, leaving an oxygen-bearing group in its place.

This was the wider meaning of the discovery. A single natural raw material, diosgenin, could feed the female hormone line (progesterone), the male hormone line (testosterone) and, as later chemists showed, many more. A 2024 review lists diosgenin as an industrial starting material for progesterone, testosterone, dexamethasone, DHEA and norethindrone, among other drugs (Pathak and Negi, 2024). Cortisone made from diosgenin in 1951, and norethindrone, the progestin of early oral contraceptives, made the same year, are the subject of the wing’s After Marker page.

The process runs only in the laboratory. Diosgenin becomes progesterone through Marker’s reagents, heat and oxidation steps, not inside a plant or a person. A 2001 double-blind, placebo-controlled trial of a wild yam cream in 23 menopausal women found no change in serum or salivary progesterone or in any other hormone measured, and no difference from placebo in symptoms (Komesaroff et al., 2001); that trial is discussed further on the Mexican yams page.

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9. No Patents: An Open Process

Marker took out no patents on the degradation. He published the chemistry step by step in the Journal of the American Chemical Society, where any chemist could read and repeat it. Accounts differ on how deliberate this was. According to the ACS booklet, Parke-Davis, which funded his work at Penn State, delayed filing patent applications past a deadline Marker had set, 1 December 1943, and when the deadline passed he refused to assign the rights to anyone. He resigned from Penn State on that same date.

The effect of an open process was that the method was public. When the Mexican steroid industry grew up in the 1940s and 1950s, the basic chemistry it relied on had already been published in full. Marker’s later life, including his part in founding a Mexican company in 1944 and his departure from chemistry in 1949, is told on the Life and Career page.

The decision also shaped how Marker was remembered. For decades he was a half-forgotten figure; a 1987 student newspaper profile called him “The Forgotten Man of Chemistry”. In 1999 the American Chemical Society and the Sociedad Química de México designated “The ‘Marker Degradation’ and Creation of the Mexican Steroid Hormone Industry, 1938–1945” an International Historic Chemical Landmark, with plaques at Penn State and in Mexico City.

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10. The 1947 Summary Paper

Marker’s sapogenin work appeared at first as a long run of short papers, numbered in his series “Sterols” and, within it, “Sapogenins”. Over his years at Penn State he published more than 160 papers in the steroid field with 32 or 33 students and postdoctoral workers, many of whom went on to industry. In 1947, after he had left the university, the work was collected in a single paper, “Steroidal sapogenins”, in the Journal of the American Chemical Society (Marker, Wagner, Ulshafer, Wittbecker, Goldsmith and Ruof, 1947).

The paper runs from page 2167 to page 2230 — about sixty pages, an unusual length for the journal. It gathered the structures of the sapogenins Marker and his group had studied, the plants they came from, and the reactions that turned them into hormone intermediates.

From paper to industry

By 1947 the chemistry described in the summary paper was already being used on an industrial scale in Mexico, on diosgenin from wild yams rather than on sarsaparilla or beth root. Marker himself left chemistry two years later, aged 47. The modern industry has since moved on: today most steroid drugs are made by microbial conversion of plant sterols combined with chemistry. The idea Marker proved in 1939 — that a plant’s own steroid could be trimmed into a human hormone — is the foundation it was built on.

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Key Research Papers

  1. Marker RE, Rohrmann E. Sterols. LIII. The Structure of the Side Chain of Sarsasapogenin. J Am Chem Soc. 1939;61(4):846-851. DOI: 10.1021/ja01873a020
  2. Marker RE, Rohrmann E. Sterols. LXXXI. Conversion of Sarsasapogenin to Pregnanediol-3(α),20(α). J Am Chem Soc. 1939;61(12):3592-3593. DOI: 10.1021/ja01267a513
  3. Marker RE. Sterols. CXIII. Sapogenins. XLII. The Conversion of the Sapogenins to the Pregnenolones. J Am Chem Soc. 1940;62(12):3350-3352. DOI: 10.1021/ja01869a024
  4. Marker RE, Tsukamoto T, Turner DL. Sterols. C. Diosgenin. J Am Chem Soc. 1940;62(9):2525-2532. DOI: 10.1021/ja01866a072
  5. Marker RE, Krueger J. Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone. J Am Chem Soc. 1940;62(12):3349-3350. DOI: 10.1021/ja01869a023
  6. Marker RE. Sterols. CV. The Preparation of Testosterone and Related Compounds from Sarsasapogenin and Diosgenin. J Am Chem Soc. 1940;62(9):2543-2547. DOI: 10.1021/ja01866a077
  7. Tsukamoto T, Ueno Y. Untersuchung der Glykoside von Dioscorea Tokoro Makino (I. Mitteilung). Yakugaku Zasshi. 1936;56(10):802-807. DOI: 10.1248/yakushi1881.56.10_802
  8. Marker RE, Wagner RB, et al. Steroidal sapogenins. J Am Chem Soc. 1947;69(9):2167-2230. PubMed PMID: 20262743
  9. Seeman JI. Russell Earl Marker and the Beginning of the Steroidal Pharmaceutical Industry. Chem Rec. 2023;23(4):e202300048. PubMed PMID: 36995067
  10. Lehmann PA, Bolivar A, Quintero R. Russell E. Marker. Pioneer of the Mexican steroid industry. J Chem Educ. 1973;50(3):195-9. PubMed PMID: 4569922
  11. Christ B, Xu C, Xu M, Li FS, Wada N, Mitchell AJ, Han XL, Wen ML, Fujita M, Weng JK. Repeated evolution of cytochrome P450-mediated spiroketal steroid biosynthesis in plants. Nat Commun. 2019;10(1):3206. PubMed PMID: 31324795
  12. Pathak N, Negi AS. Plant based steroidal and triterpenoid sapogenins: Chemistry on diosgenin and biological aspects. Eur J Med Chem. 2024;279:116915. PubMed PMID: 39366126
  13. Komesaroff PA, Black CV, Cable V, Sudhir K. Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women. Climacteric. 2001;4(2):144-50. PubMed PMID: 11428178

PubMed Topic Searches

  1. Diosgenin, progesterone and history
  2. Dioscorea and diosgenin
  3. Steroidal sapogenins
  4. Spiroketal steroid biosynthesis

Further Reading

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Connections