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Vol. 285 No. 7

MEDICAL INTELLIGENCE-GREENWALD ET AL

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Table 1. Adenocarcinoma of the Vagina and Maternal Use of Synthetic Estrogen in Patients Reported to the New York State Cancer Registry, 1950-1970.

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of advanced disease. Case 2 had symptoms for 18 months before diagnosis and is now in the hospital recovering from an anterior exenteration, total vaginectomy and pelvic lymph-node dissection, with creation of an ileal vagina.

Case 5 had symptoms for 10 months before diagnosis. She was treated with radical hysterectomy, total vaginectomy with ovaries left intact and development of an artificial vagina. Her physician believes that she is probably cured.

None of the mothers of the eight control patients received stilbestrol therapy during pregnancy. No controls were obtained for Case 1, born in New York City.

DISCUSSION

The observation that mothers of the five patients with adenocarcinoma of the vagina had synthetic estrogens during pregnancy confirms the previously reported association. Although we do not know how frequently these compounds were used, obstetricians in several Upstate New York cities believe that stilbestrol for threatened abortion was used fairly widely and in large doses during the early 1950's and that use has since declined. Dienestrol and stilbestrol are nonsteroidal estrogens, similar in structure and dose.

Large doses of stilbestrol for threatened abortion were recommended by two major pharmaceutical companies in the 1950 Physicians' Desk Reference. Dosages were similar to those recommended by the Smiths, starting in the seventh week with 5 mg per day and increasing stepwise to 135 mg per day at the 35th week, when stilbestrol was discontinued. In other conditions such as senile vaginitis the rec

ommended dose range was 0.1 to 1 mg daily, and for suppression of lactation, the recommended dose was 15 mg daily, for two to four days.

The uniformity of histologic pattern supports the possibility of common etiology. The clustering of patients by date of birth within a three-year period when synthetic estrogen therapy for threatened abortion was common suggests that the cancer was related to maternal therapy rather than to threatened abortion in the absence of therapy. Control mothers had noncomplicated pregnancies and no synthetic estrogen therapy.

The true risk of miscarriage in these pregnancies could not be definitely established. Records for mothers of Cases 1 and 3 mentioned only firsttrimester spotting or staining, and there was no history of previous abortion. Case 2's mother had had a previous miscarriage and stated that she had spotting during the pregnancy in question (not mentioned in the obstetric record). Case 4's mother had had three previous abortions and spotting and cramps during this pregnancy, and Case 5's mother had had no previous miscarriages, but stated that therapy was begun because of a gush of bright-red blood, which continued intermittently for one week. Since the risk of miscarriage in one or more patients may have been low, it appears that synthetic estrogens in the absence of threatened abortion may lead to vaginal cancer.

The New York State Cancer Registry reviewed records from 1950 turough 1970. All vaginal acienocarcinomas were diagnosed during the period 1966 through 1971, with three of the five being diag nosed last year or this year. This raises concern about the future. It is not known how many more

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THE NEW ENGLAND JOURNAL OF MEDICINE

vaginal carcinomas will be developing, whether other types of cancer will also develop in men or women, or whether a longer induction period may be present for those who received a smaller dose.

There can no longer be doubt that synthetic estrogens are absolutely contraindicated in pregnancy. Young women with persistent irregular bleeding should have careful intravaginal inspection to rule out possible neoplastic disease.

We are indebted to Drs. Sidney B. Doolittle and Robert E. L. Nesbitt, Jr., Syracuse, and Dr. James N. Nicklas, Glen Cove, Mrs. Katherine Richard, public-health nurse, St. Lawrence County, and Mr. Joseph M. Cuneo, biostatistician, Nassau County Health Department, New York, for reporting of patients and assistance with this study.

REFERENCES

1. Herbst AL, Ulfelder H. Poskanzer DC: Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878-881, 1971

2 Langmuir AD: New environmental factor in congenital disease: N Engl J Med 284:912-913, 1971

3. Smith OW: Diethylstilbestrol in the prevention and treatment of complications of pregnancy. Am J Obstet Gynecol 56:821-834. 1948

4. Physicians' Desk Reference to Pharmaceutical Specialties and Biologicals (PDR). Rutherford, New Jersey, Medical Economics, Inc. 1950, pp 468, 500

5. Herbst AL, Scully RE: Adenocarcinoma of the vagina in adolescence: a report of 7 cases including 6 clear-cell carcinomas (socalled mesonephromas). Cancer 25:745-757, 1970

6 Goth A: Medical Pharmacology: Principles and concepts. Second edition. St Louis, CV Mosby Company, 1964, pp 426-427

NOTES OF A BIOLOGY-WATCHER

A Fear of Pheromones

LEWIS THOMAS, M.D.

WHAT are we going to do if it turns out that

we have pheromones? What on earth would we be doing with such things? With the richness of speech, and all our new devices for communication, why would we want to release odors into the air to convey information about anything? We can send notes, telephone, whisper cryptic invitations, announce the giving of parties, even bounce words off the moon and make them carom around the planets. Why a gas, or droplets of moisture made to be deposited on fenceposts?

Comfort has recently reviewed the reasons for believing that we are, in fact, in possession of anatomic structures for which there is no rational explanation except as sources of pheromones tufts of hair, strategically located apocrine glands, unaccountable areas of moisture. We even have folds of skin here and there designed for the controlled nurture of bacteria, and it is known that certain microbes eke out a living, like 18th-century musicians,

Address reprint requests to Dr. Thomas at the Department of Pathology. Yale University School of Medicine, 310 Cedar St., New Ha ven, Conn. 06510.

Aug. 12, 1971

producing chemical signals by ornamenting th... products of their hosts.*

Most of the known pheromones are small, simpl.. molecules, active in extremely small concentrations Eight or 10 carbon atoms in a chain are all that are needed to generate precise, unequivocal directions about all kinds of matters when and where t cluster in crowds, when to disperse, how to behav to the opposite sex, how to ascertain what is the opposite sex, how to organize members of a societ in the proper ranking orders of dominance, how to mark out exact boundaries of real estate, and how to establish that one is, beyond argument, one's sel: Trails can be laid and followed, antagonists frightened and confused, friends attracted and enchanted.

The messages are urgent, but they may arrive, for all we know, in a fragrance of ambiguity. "At home, 4 p.m. today," says the female moth, and releases a brief explosion of bombykol, a single molecule of which will tremble the hairs of any male within miles and send him driving upwind in a confusion of ardor. But it is doubtful if he has an awareness of being caught in an aerosol of chemical attractant. On the contrary, he probably finds suddenly that it has become an excellent day, the weather remark.bly bracing, the time appropriate for a bit of exer cise of the old wings, a brisk turn upwind. En route, traveling the gradient of bombykol, he notes the presence of other males, heading in the same direction, all in a good mood, inclined to race for the sheer sport of it. Then, when he reaches his destination, it may seem to him the most extraordinary of coincidences, the greatest piece of luck: "Bless my soul, what have we here!"

It has been soberly calculated that if a single female moth were to release all the bombykol in her sac in a single spray, all at once, she could the oretically attract a trillion males in the instant. This is, of course, not done.

Fish make use of chemical signals for the identification of individual members of a species. and also for the announcement of changes in the status of certain individuals. A catfish that has had a career as a local leader smells one way, but as soon as he is displaced in an administrative reorganiza tion, he smells differently, and everyone recognizes the loss of standing. A bullhead can immediately identify the water in which a recent adversary has been swimming, and can distinguish between this fish and all others in the school.

There is some preliminary, still fragmentary evidence for important pheromones in primates. Shortchain aliphatic compounds are elaborated by female monkeys in response to estradiol, and these are of consuming interest to the males. Whether there ar other sorts of social communication by pheromones among primates is not known.

The possibility that human beings are involved in this sort of thing has not attracted much attention until recently. It is still too early to say how it will

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DRUG'S USE LINKED TO ADENOCARCINOMA IN THE OFFSPRING

We wish to bring to the attention of all physicians, hospitals, and medical personnel an important possible toxic effect of diethylstilbestrol reported for the first time in April 1971 by Herbst, et al. From their studies the authors concluded that maternal ingestion of diethylstilbestrol during pregnancy appears to increase the risk of vaginal adenocarcinoma developing years later in the offspring exposed. The authors studied eight cases of adenocarcinoma of the vagina in patients born between 1946 and 1951. The malignancies were identified and treated between 1966 and 1969. In seven of the eight cases, there was a history of maternal use of diethylstilbestrol. Because this type of malignancy in young girls had rarely been reported previously, the authors conducted a retrospective investigation in an attempt to find factors that may be associated with such malignancy in this age group. Four matched controls were established for each patient and the data obtained were subjected to statistical analysis. A statistically significant relationship was observed for three variables: diethylstilbestrol given during pregnancy (p=.00001), bleeding in that pregnancy (p less than .05) and prior pregnancy loss (p-less than .01). It is obvious that the most significant of the variables is the administration of

diethylstilbestrol during pregnancy.

Since publication of this study, five additional cases of this malignancy associated with the maternal use of diethylstilbestrol have been reported by Greenwald, et al2. Dr. Herbst, in a recent communication to FDA, has reported an additional 15 cases associated with use of this drug, bringing the total number of known cases to 27. It must be emphasized that this type of epidemiologic study defines only an association and not necessarily a cause-and-effect relationship. Further studies are underway to clarify the significance of these findings.

In the meantime, the FDA is initiating the

1. Herbst, et al Adenocarcinoma of the Vagina - New England Journal of Medicine - Volume 284, Number 16 (April 22, 1971).

following precautionary actions:

1. All manufacturers of DES or closely related congeners (dienestrol, hexestrol, benzestrol, promethestrol) are being notified that appropriate changes will be required in the labeling for such drugs. This change will consist in the listing of pregnancy as a contraindication to the use of diethylstilbestrol and the other above-mentioned compounds.

2. All other estrogens will be required to have the following WARNING in their labeling: "A statistically significant association has been reported between maternal ingestion during pregnancy of diethylstilbestrol and the occurrence of vaginal carcinoma developing years later in the offspring. Whether such an association is applicable to all estrogens is not known at this time. In any event, estrogens are not indicated for use during pregnancy."

3. Epidemiological studies are being initiated to determine the true incidence of this disease in young women, the number at risk, the characteristics of patient populations with this malignancy, and the probability of a cause-and-effect relationship.

Both FDA and the medical profession face a responsibility to help determine whether this reported association constitutes a cause-and-effect relationship. We ask that all physicians consider appropriate steps to assist FDA case-finding and to protect any patients who might be at risk.

It may be possible to trace the offspring of those mothers who received DES during pregnancy. All physicians should be especially alert for young women whose mothers may have received hormonal therapy during pregnancy, particularly those young women who may be experiencing irregular vaginal bleeding. The association should be a routine consideration for physicians whose practice includes young women.

This is a previously unsuspected health problem. Further information is essential to the FDA and to the medical profession. We ask your help in reporting any cases you encounter for entry in a case registry.

2. Greenwald, et al Vaginal Cancer After Maternal Treatment with Synthetic Estrogens - New England Journal of Medicine, Volume 285, Number 7, (August 12, 1971).

FDA will take every possible step to insure that you are kept abreast of new information as soon as it can be gathered and analyzed.

reporting form is printed in this bulletin. FDA will forward a supply of forms to each practicing physician as soon as they are printed. Facsimile For your convenience, an adverse reaction forms are acceptable.

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