An Epidemic IgnoredEndometriosis linked to dioxinand immunologic dysfunction

Endometriosis is a mysterious disease. Often misdiagnosed, itssymptoms are varied, its cause

obscure, its cure unknown. But some ofthe secrets of this illness, which aÜicts10 percent of women in their childbear-ing yearsÑabout 5.5 million people inthe U.S. and CanadaÑare being unrav-eled. A report has linked the illness todioxin exposure; other research sug-gests that immune dysfunction plays arole. ÒThis is a pivotal time for thestudy of endometriosis,Ó says Sherry E.Rier, an immunologist at the Universi-ty of South Florida who led the teamthat conducted the work on dioxin.

The discoveries coincide with the rec-ognition that the prevalence of endo-metriosis may be rising and becomingmore common in young women. ÒThepublic health impact of this disease isenormous,Ó says JeÝ Boyd, a moleculargeneticist at the National Institute ofEnvironmental Health Sciences. ÒIt af-fects millions and millions of people,but it does not garner the resources that

24 SCIENTIFIC AMERICAN April 1994

and Groller then teamed up to writeThe WarriorÕs Edge: Front-Line Strate-

gies for Victory on the Corporate Battle-

Þeld. Published in 1990, the book tellscorporate climbers how psychic powerscan help them rise to the top.

Since then, the Morrises and Alexan-der have had a falling-out, with eachside accusing the other of hogging cred-it for the concept of nonlethality. ÒAlex-ander was ripping oÝ our ideas andsending them up the chain of com-mand,Ó Janet Morris says. The Morrisesalso charge Alexander and other mili-tary oÛcials with trying to keep thenonlethal program under wraps byclassifying it.

Alexander acknowledges that manyaspects of nonlethal research are indeedclassiÞedÑincluding the budget of theprogram he oversees at Los Alamos (alaboratory spokesperson would say onlythat the Þgure is Òin the millionsÓ). Buthe contends that although he is in favorof relaxing restrictions, the decision isnot his to make. He also denies coopt-ing ideas from the Morrises. He assertsthat he wrote a paper on nonlethalityÞve years ago and that the basic con-cept had been discussed by defense an-alysts since at least 1972. ÒClaiming tohave invented this concept is analo-gous to claiming to have developed civ-il rights,Ó he declares. ÑJohn Horgan

KUWAIT PRIZE 1994Invitation to Nominations

The Kuwait Prize was institutionalized to recognize distinguishedaccomplishments in the arts, humanities and sciences.

The Prizes are awarded annually in the following categories:A. Basic SciencesB. Applied SciencesC. Economics and Social SciencesD. Arts and LettersE. Arabic and Islamic Scientific Heritage

The Prizes for 1994 will be awarded in the following fields:A. Basic Sciences: Molecular BiologyB. Applied Sciences: Nutrition and Related DiseasesC. Economics and Social Sciences: Development of Arab Human ResourcesD. Arts and Letters: Comparative LiteratureE. Arabic and Islamic Scientific Heritage: Mining and Metallurgy

Foreground and Conditions of the Prize:1. Two prizes are awarded in each category:

* A Prize to recognize the distinguished scientific research of a Kuwaiti,and,* A Prize to recognize the distinguished scientific research of an Arabcitizen.

2. The candidate should not have been awarded a Prize for the submittedwork by any other institution.

3. Nominations for these Prizes are accepted from individuals, academicand scientific centres, learned societies, past recipients of the Prize,and peers of the nominees. No nominations are accepted from politicalentities.

4. The scientific research submitted must have been published duringthe last ten years.

5. Each Prize consists of a cash sum of K.D. 30,000/-(U.S. $100,000/-approx.), a Gold medal, a KFAS Shield and a Certificate of Recognition.

6. Nominators must clearly indicate the distinguished work that qualifiestheir candidate for consideration.

7. The results of KFAS decisions regarding selection of winners are final.8. The papers submitted for nominations will not be returned regardless

of the outcome of the decision.9. Each winner is expected to deliver a lecture concerning the contribution

for which he was awarded the Prize.

Inquiries concerning the Kuwait Prize and nominations including complete curriculum vitae and updated lists of publications by the candidate withfour copies of each of the published papers should be received before31/10/1994 and addressed to:

The Director GeneralThe Kuwait Foundation for the Advancement of Sciences

P.O. Box: 25263, Safat-13113, KuwaitTel: +965 2429780 Fax: +965 2415365

Look for the Reader Service Directory (page 105) for additional information

from the advertisers in this issue.

Copyright 1994 Scientific American, Inc.

more lethal diseases do, even thoughthey aÝect a lot fewer people.Ó

Endometriosis is a disease of rene-gade cells. Tissue from the uterine lin-ing proliferates in other areas of thebody, such as the bladder, intestine or,in rare cases, the lung. How these cellsreach the distant organs remains un-known. One theory holds that ratherthan draining out of the body, menstru-al blood ßows backward into the fallo-pian tubes and moves on from there.Regardless of where they end up, endo-metrial cells continue to respond to thehormonal pulses of the menstrual cy-cle. When estrogen levels increase, thecells act as the uterine lining does, bybuilding up; when progesterone rises,they slough oÝ, causing internal bleed-ing. This shedding can cause great pain.

The discomfort caused by endome-triosis has often been considered anunfortunate but untreatable aspect ofwomenÕs biology: excruciating menstru-al periods are just some womenÕs lot.For that reason, physicians frequentlydid not recognize the disease until itwas severe, often requiring the removalof uterus and ovaries. The Endometrio-sis Association, a Milwaukee-based or-ganization, reports that 70 percent ofwomen diagnosed with endometriosiswere initially told by their doctors that

there was no physical reason for theirpain. Black women were told a slightlydiÝerent story: 40 percent of those suf-fering intense pelvic pain that provedto be endometriosis were told they hada sexually transmitted disease.

Identifying endometriosis has be-come easier in the past decade becauseit is more widely recognized and be-cause laparoscopyÑthe insertion of atiny viewing tube into the abdomenÑfacilitates seeing the growths. But untilrecently, the enigma of its etiologyseemed impenetrable. The disease wasassociated with many variables, includ-ing immune disorders such as lupus,with cancer, with the use of intrauter-ine devices ( IUDs) and, most consis-tently, with infertility.

Between 30 and 40 percent of wom-en who are treated for infertility haveendometriosis, although it is not clearwhich condition, if either, causes theother. For many years, womenÕs careerswere deemed responsible. Researchersannounced that delaying childbirth wasthe problem: the more periods a wom-an has in her life, the more susceptibleshe is. But Òit is very easy to demolishthat argument,Ó comments Mary LouBallweg, president and executive direc-tor of the Endometriosis Association.Ballweg says many women experience

their Þrst symptoms in their teens: 41percent of women diagnosed with en-dometriosis had symptoms before theage of 20. ÒI donÕt think we are goingto want to tell 13-year-olds to go outand get pregnant as a form of preven-tion,Ó she adds.

Today Òendometriosis appears to bemore of an immunologic than a repro-ductive disorder,Ó Ballweg explains.ÒAnd when you look at the dioxin liter-ature, everything starts falling intoplace.Ó Dioxins are pollutants createdin certain industrial processes; themost potent of the 75 kinds is 2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD.The link between TCDD and endome-triosis was made last November, whenRier reported in Fundamental and Ap-

plied Toxicology that 79 percent of thefemales in a rhesus monkey colony ex-posed to dioxin developed endometri-osis. The monkeys were exposed 15years ago and subsequently monitored.

After three of the monkeys werefound to have widespread endometri-osis, the rest of the colony was exam-ined. The prevalence and severity ofthe disease correlated with exposure:43 percent of the animals who receivedÞve parts per trillion (ppt) of dioxin de-veloped moderate to severe endometri-osis, as did 71 percent of those exposed

26 SCIENTIFIC AMERICAN April 1994 Copyright 1994 Scientific American, Inc.

to 25 ppt. (An average person has aboutseven ppt of TCDD; the people mostcontaminated in the 1976 industrial ac-cident in Seveso, Italy, had 56,000 pptin their blood.)

Other Þndings support the dioxinconnection. In 1992 German research-ers announced that women with highblood levels of polychlorinated biphe-nyls (PCBs), compounds related to di-oxins, have a greater than normal inci-dence of endometriosis. Scientists atthe Department of Health and Welfarein Canada have also found that manyfemale rhesus monkeys exposed toPCBs developed endometriosis. Thesedata have not yet been published.

After RierÕs Þndings, Boyd and hiscolleagues began evaluating blood lev-els of dioxins and 200 related com-pounds in women with endometriosis.Brenda Eskenazi of the University ofCalifornia at Berkeley and Paolo Moca-relli of the University of Milan willstudy dioxin-exposed women in Seve-so. ÒThere have been a lot of studies ofoccupationally exposed males, and wereally need some on women,Ó notesLinda Birnbaum, a toxicologist at theEnvironmental Protection Agency, whostudies rodent models of the disease.

The dioxin Þndings are intriguing be-cause researchers are increasingly con-

vinced that the pollutant acts like a hor-mone, often mimicking estrogen, anddisturbs the immune system. Scientistshave observed immunologic dysfunc-tion in animals exposed to the contam-inant. At least one researcher has re-ported similar disturbances in childrenborn to dioxin-exposed mothers, al-though these data have not yet beenpeer-reviewed. The mechanisms of suchinteractions remain hidden for now,but it is evident that Òthese systems donot function alone,Ó Rier says. ÒChang-es in the endocrine system cause chang-es in the immune system.Ó

In addition to Þnding a correlationbetween dioxin and endometriosis, Rierfound immunologic changes in themonkeys that reßect those seen in peo-ple. Women with endometriosis oftenhave very aggressive macrophages, atype of immune system cell, in the peri-toneum. These macrophages secretecytokines and growth factors that canirritate endometrial cells. Rier cautionsthat the monkey data are preliminaryand that no one knows if changes inthe immune system result from dioxinor from endometriosis. Nevertheless,the research creates excitement. ÒThewhole issue of the immune system isfascinating; it is the right track,Ó con-curs David L. Olive, a reproductive en-

docrinologist at the Yale UniversitySchool of Medicine.

Another interesting aspect of the im-mune system work may clarify the re-lation between endometriosis and in-fertility. Bruce A. Lessey, a reproductiveendocrinologist at the University ofNorth Carolina at Chapel Hill, has iden-tiÞed a receptor, called beta-3, for acell-adhesion molecule absent in wom-en with endometriosis. These moleculeshave many functions, including a rolein immune response. Lessey also foundbeta-3 to be missing in some infertilewomen. Beyond potentially serving as ameans of identifying and treating en-dometriosis and infertility, informationabout beta-3 Òcould be used to make acontraceptive,Ó Lessey exclaims.

Taken together, the dioxin and im-munologic research indicates that a ful-ler understanding of endometriosis maynot be far-oÝ. In this context, the sug-gested rise in incidence could be omi-nous. Environmental distribution of di-oxin and its cousins has been spread-ing. Given Òthat dioxin is an endocrinedisrupter and that there is a tight link-age between the immune system andendometriosis, it is not inconceivablethat incidence is increasing and thatthe age of onset is decreasing,Ó Birn-baum notes. ÑMarguerite Holloway

SCIENTIFIC AMERICAN April 1994 27Copyright 1994 Scientific American, Inc.