Try, try, try again … and again

Superficially, there appears to be little in common between Janet Baum (Fig. 1), Director of the Department of Radiology at the Beth Israel Deaconess Medical Center in Boston, and the 14th Century King of the Scots, Robert the Bruce. Yet, although Janet freely admits that she had not heard of King Robert I (1274–1329), who ruled over Scotland from the declaration of his monarchy in March of 1306, until his death, allegedly from leprosy, in June of 1329, she shares the same philosophy of not capitulating in the face of defeat, rejection, or failure, as exemplified by her battle with medical journals, just over 30 years ago, to publish the novel observation that oral contraceptives steroids (OCS) induce hepatic adenomas.1 Dr. Janet Baum of the Department of Radiology at the Beth Israel Deaconess Medical Center and Harvard University. Robert de Brus, Earl of Carrick and 5th Lord Annandale, was born of Norman and Celtic ancestry on July 11, 1274, at Turnberry Castle on the Ayrshire coast, in the west of the lowlands of Scotland. Although he was a grandson of a former claimant to the throne of Scotland, Bruce wavered initially in his Scottish patriotism and even paid homage to the notorious “Hammer of the Scots,” Edward I of England. However, after the failure of William Wallace's rebellion and Wallace's own brutal execution at Edward's command (mostly depicted with Gibsonian violence and historical distortion in the 1995 movie Braveheart), Bruce, now King, fervently championed Scotland's bid for independence from England.2, 3 While hiding in a cave, demoralized after yet another bloody defeat, Bruce was heartened to press on, as Winston Churchill wrote,4 “…by the persistent efforts of the most celebrated spider in history” that succeeded in spinning its web after numerous attempts had failed. While it may be apocryphal that Bruce concluded from the imagery the maxim “If at first you don't succeed, try, try, try again,” ever since then this encouraging motto has served as a watchword against giving up without a fight. Indeed, Bruce and his followers then marched on to beat the English decisively at the Battle of Bannockburn on Mid-Summer's Day, June 24, 1314, against great odds. “Good King Robert” remains the quintessential Scottish hero for his skillful military strategy and prowess, defense of freedom, chivalry, diplomacy, and compassion. While Janet's struggle to get her assertion accepted by the medical establishment that oral contraceptives can cause liver tumors was not as epic as Bruce's quest for Scottish independence, nonetheless fortitude and great motivation were sorely needed for this very junior trainee in Radiology to not give up in the face of rejection and ridicule. The introduction of OCS, colloquially called birth control pills or The Pill, at the beginning of the decade known as the “Swinging Sixties” was somehow in tune with the changing social philosophy of the times concerning personal freedom and a new liberalism (to which it may have even contributed) and was obviously a seminal event in the graphic history of contraception. Chinese woman drank mercury to achieve contraception two millennia before the current era, Greeks took diluted copper ore, Italians imbibed a tea of willow leaves with mule's hoof, and Africans sampled gunpowder with camel's foam, while women indigenous to Canada cocktailed on alcohol tinctures of dried beaver testicles. The modern reliance on synthetic progesterones stems from the observation made in the late 1930s that progesterone inhibits ovulation in rabbits. Early efforts to synthesize mammalian progesterone and other hormones started with saponins extracted from the Dioscorea species of Mexican yams, using syntheses invented by the maverick American biochemist Russell Marker at the laboratories of Syntex (acquired by Novartis in 1994) that he helped found in Mexico City. In 1951, at these same laboratories, the renowned and colorful Vienna-born organic chemist turned novelist, playwright, poet, and philosopher Carl Djerassi (Professor Emeritus, Stanford University 2002) succeeded in producing and patenting an orally available synthetic progesterone, norethindrone, for which he received many awards and ultimately the title “Father of the Contraceptive Pill.”5 Contemporaneously, Frank B. Colton, a research chemist at GD Searle—the company that produced the first anabolic steroid norethandrolone, the diuretic spironolactone, and many other synthetic steroids—fabricated norethynodrel, which combined with what was initially a contaminant, the synthetic estrogen mestranol, was approved as Enovid by the FDA in 1957 for treating menstrual disorders and infertility.6 In 1960, Enovid was FDA-approved as the first birth control pill in the United States, following the pioneering clinical trials conducted by Harvard reproductive physiologist Gregory Pincus and Harvard obstetrician and gynecologist John Rock.7 Pincus and Rock were supported by funds garnered by birth control activist and founder of the Planned Parenthood Federation of America, Margaret Sanger (1879-1966), from Katherine Dexter McCormick (1875-1967), suffragette and widow of the heir to the International Harvester fortune.8 Clearly OCS were the most successful contrivances against conception since the invention of celibacy, and by 1967, upwards of 12.5 million women worldwide were taking them. By 1968, sales reached $150 million, despite growing evidence of adverse effects of these high-dose preparations, such as weight gain, headaches, nausea, and, more notoriously, hypertension, thromboses (exacerbated by cigarette smoking), strokes, and heart attacks,9 as publicized in Barbara Seaman's book, The Doctor's Case Against the Pill.10 Against this backcloth, Janet Baum comes to the scene with a new and heretofore unexpected complication of OCS use.1 The index case of an OCS-associated hepatic adenoma came to the attention of Baum by way of a liver resection specimen that she processed during a brief elective intern rotation in Pathology, prior to residency training in Radiology at her alma mater, the University of Michigan at Ann Arbor. The rarity of that benign liver tumor in adults prompted a manual search of 40 years' worth of pathology records that brought the yield to 3 cases, all of whom were young women diagnosed within the previous 5 or 6 years. Intuitive deduction linked this new disease of the sixties to the contemporary lifestyle of young women, and especially to the Pill that each of these patients had used for 6 months to 5 years. The submission to the Journal of the American Medical Association (JAMA) in April of 1970 by Baum and her mentors in the Departments of Pathology and Radiology was rejected with ridicule. How reminiscent of many bad predictions in science, technology, and other human endeavors by experts and celebrities who would be expected to know better.11 William Thomson, Lord Kelvin, the eminent British scientist, declared in 1899 that “Radio has no future, heavier-than-air-flying machines are impossible and X-rays will prove to be a hoax.” Irving Fisher, Professor of Economics at Yale University, concluded in 1929 that stocks had reached what looked like a permanent high plateau, and Gary Cooper smugly expressed satisfaction at his decision not to take the leading role in Gone with the Wind, as he relished the prospect of Clark Gable “…falling flat on his face…” in that part, instead of him. Meanwhile similar cases continued to be discovered in the Ann Arbor, MI, area, partly because of the publicity given to Baum's observation by the formidable Chair of Surgery, Charles G. Child 3rd, who was an unexpected professional ally of the diminutive radiology resident. Baum and colleagues collected 7 cases from their small community area that they mistakenly termed “benign hepatomas,” in women aged 25 to 39 years who presented with abdominal pain or a self-palpated mass, 5 of whom had sudden intraabdominal hemorrhage. After trying to publish in JAMA, Baum tried again with the New England Journal of Medicine and tried again with Radiology before her try with the Lancet gained acceptance and rapid publication.1 Baum's contribution was not lost on Gerald Klatskin in his review of the possible relationship of hepatic tumors to the use of oral contraceptives,12 especially since the first two case reports13, 14 of the occurrence did not comment on a possible etiological relationship. Sixteen months after publication in the Lancet by Baum et al.,1 JAMA published a report in its Medical News section about the possible relationship between OCS and benign primary tumors of the liver that sometimes rupture with subsequent life-threatening hemorrhage,15 but the journal made no mention of Baum's landmark article, to the understandable annoyance of its lead author.16 Prior to the widespread propagation of high-dose OCS, hepatic adenomas were considered to be few and far between, especially in adults. Berkheiser17 found only 1 case of hepatic adenoma, in a 79-year-old woman, among 2,176 autopsies performed in Harrisburg, PA, between 1949 and 1958 (to which he added a case of recurrent hepatic adenoma 6 years after successful resection, in a 71-year-old woman), and Henson et al.18 found only 4 cases in the surgical files of the Mayo Clinic between 1907 and 1954, in a 5-year-old girl, 2 young women (ages 28 and 39), and a 64-year-old man. As noted earlier, only 2 more cases were reported, in 197113 and 1972,14 which begs the question whether the 67 cases of hepatic adenoma reviewed by Warvi19 in 1944 were truly reliably distinguished from regenerative nodules and focal nodular hyperplasia. The paucity of cases before 1973 contrasts with what Klatskin called an avalanche of reports12 after Baum's study, which also prompted the creation of registries of such tumors.20, 21 Hepatic adenomas occur not only in pediatric and adult patients with glycogen storage diseases (types I and III)22, 23 but also spontaneously in children, even in the neonatal period,24 and they are sometimes associated with unusual clinical features, such as generalized osteoporosis, urticaria, and koilonychias.25 Hepatic adenomas have been found in alcoholic men26 and during the long-term administration of androgenic steroids for the treatment of various anemias27, 28 and testosterone deficiency,29 even in men with high circulating levels of endogenous sex steroid hormones30 and in patients receiving growth hormone for Turner's syndrome.31 Nonetheless, hepatic adenoma is still predominantly a disease of female gender, for even in series that include men, the latter are outnumbered 4:1.32 The female liver seems to be pathology prone, judging by afflictions such as alcoholic liver injury, nonalcoholic fatty liver disease, primary biliary cirrhosis, autoimmune hepatitis, and gallstones, which are all more common in women than in men, not to mention the catalogue of pregnancy-associated hepatopathies. Despite how much is understood about the pathogenesis of these female-dominant liver disorders and about the effects of sex steroid hormones on the liver,33-36 the pathogenesis of OCS-induced hepatic adenoma is still not known. The risk of developing hepatic adenoma increases with the dose and duration of OCS therapy, although lesions can occur with only 6 months' exposure.1 The relative risk of developing hepatic adenoma with high-dose OCS was 9 after 1 year, increasing 100-fold after 5 years and 500-fold after 7 years, with an overall incidence of 3 or 4 cases per 100,000.37 Withdrawal of OCS often leads to tumor regression,38 but this is not invariable,39 and there is, occasionally, transformation to hepatocellular carcinoma.40 Sex steroids appear to be tumor inducers,41 but analyses of adenomas for steroid receptor expression have given mixed results,42 as have studies on the Wnt signaling pathway43 that is important in both hepatocellular carcinoma and hepatoblastoma. The urgency of knowing how OCS cause liver tumors has diminished somewhat since the prevalence of adenomas appears to have reduced44 along with other complications of OCS use, following the universal reduction in OCS doses. A little over a year after the publication of the 1973 Lancet article,1 Syntex convened a meeting at the Mount Sinai School of Medicine in New York City, under the chairmanship of Hans Popper, to discuss the impact of Baum's discovery, and this meeting resulted in a labeling change for OCS products to include a warning concerning the risk of adenoma complications, notably pain and bleeding. Baum's persistence bore fruit in helping to bring about an awareness among patients, physicians, and the pharmaceutical industry of a potentially life-threatening adverse effect of a class of drugs with worldwide distribution. How much better to follow Bruce's advice to try, try, try again in the face of opposition than to follow the negative conclusion of Homer Simpson, who said, “You tried your best and you failed miserably. The lesson is ‘never try.’ ” The author thanks Dr. Janet Baum for taking so much time to relate in depth the history of her discovery of oral contraceptive–induced hepatic adenomas, and Dr. Stuart Gordon for his introduction to Janet Baum. Once again, thanks go to Margie Myers for literature retrieval and manuscript preparation.

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