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Effects of oral and intrauterine administration of contraceptives on the uterus
EFFECTS OF O R A L A N D INTRAUTERINE A D M I N I S T R A T I O N OF CONTRACEPTIVES ON THE UTERUS William B. Ober, M.D.*
Abstract Combined regimen contraceptive steroids produce precocious endometrial secretion, followed by involution leading to a suppressed endometrium with small tubular glands and failure of spiral arterioles to develop; decidua-like stromal clmnges are dose related as is dilatation of venules. Thrombosis of the latter, perhaps estrogen mediated, leads to local tissue infarction and is the proximate cause of "breaktllrough bleeding." Sequential regimen contraceptive steroids lead to retarded endometrial secretion, failure of spiral arterioles to develop, and a weak decidua-like stromal transformation. Contraceptive steroids occasionally produce polypoid lesions of the endocervix with atypical microglandular hyperplasia. T h e r e are coriflicting reports about the effects of contraceptive steroids on the squanmus epitlmlium of the exocervix, but they neither protect against cancer nor cause it in the usually accepted sense. Uterine leiomyomas may exhibit increased cellularity and bizarre, hyperchromatic nuclei or mutinucleation in women receiving contraceptive steroids. Both polyethylene and metal-containing intrauterine devices may initiat(; inflamnmtory responses in tlm endometrium varying fi'om mild t o severe, related to tim time tim device Ims been in contact with the mucosa. Salpingitis and ectopic pregnancy are increased in frequency in device users.
Clinical trials of synthetic progestagens for contraception began in the late 1950's, and shortly thereafter polyethylene intrauterine devices were developed for the same purpose., By the end of the 1960's, a number of synthetic steroids, both estrogens and progestagens, were approved for both safety and efficacy. The ingenuity of physicians and
manufacturers combined to produce a wide variety of shapes and sizes of intrauterine devices made from either polyethylene or stainless steel, and in the 1970's copper became a prominent element in such devices. The social impact of relatively safe contraception was enormous, and sociologists and otlmr pundits spoke glibly of the "sexual revolution."
*l'mfcssor of l'athology, Mount Sinai School of Medicine of tile City Universityof New York. Attendingl'athologist,Beth Israel Hospital,New York, New York.
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HUMAN PATHOLOGY--VOLUME 8, NUMBER 5 September 1977 Needless to say, one does not adntinister drugs on a continuing basis o1" insert a 9foreign body into the womb without incurring anatomical alterations, which are the subject of this essay. EFFECTS OF SYNTHETIC STEROIDS (ORALLY ADMINISTERED CONTRACEPTIVES)
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First, a word about orthography. Tile term progestogen was initially advanced to describe the class of synthetic steroids with progesterone-like activity. T h e suffix -ogen was used in conformity with its usage in such familiar terms as estrogen and androgen. But these are derived purely fiom Greek roots, whereas progesterone combines the Latin base gesta-, from gestate, to bear (a child), with the chemical suffix -one, which denotes a ketonic group in the molecule. Pro- and gesta- indicate something that promotes pregnancy or child bearing, and we speak of progesrational effects. The proper stem, therefore, is progesta-, to which tile suffix -gen may be added. T h e substances used in contraceptive "pills" are not naturally occurring hormones but products of the organic chemist's laboratory. Althougll their biologic properties are similar to those of endogenous estrogens and progesterone, neither their biologic nor morphologic responses are identical. Receptor sites sufficiently sensitive to discriminate between estradiol-17fl (active) and its stereoisomer, estradiol-17o~ (inactive), can also distinguish between the 19-nor steroids or 17-hydroxyprogesterone derivatives such as 6-medroxyprogesterone and naturally occurrit~g progesterone. Within limits, the effects of synthetic steroids are time-dose related, but even more ilnportant is synchronization of the steroid stimulation. Two types of regimen lmve been developed for contraception: (1) the combined regimen, ' in which a synthetic progestagen was combined with a synthetic estrogen into a single tablet taken for 20 or 21 days starting five days after the onset of bleeding, and (2) the sequential regimen in which an estrogen was taken for 15 or 16 days followed by six o1" five days in which the tablet con-
tained both a progestagen and an estrogen at tile same dosage. According to a third regimen, used for patients with pelvic endometriosis, tile combination tablet was taken continuously, without withdrawal for bleeding, and was often administered in stepwise monthly increments. One should remember that if ovulation is suppressed, the bleeding that follows withdrawal of the drug is not true menstruation. It is opportune to mention at this point that sequential medications have been voluntarily withdrawn from the market because they were less effective than combination therapy and were possibly associated with increased risks of thromboentbolism and endometriai adenocarcinoma (q.v.). 1 It is not widely appreciated that the effects of contraceptive steroids extend beyond their usual target organ. Irey, Manion, and Ta)'lor 2 and later Irey and Norris s described vascular lesions, predominantly intimal proliferation of a myxoid, fibrous, or celhtlar character, sometimes complicated by thrombosis, occurring in women taking contraceptives orally, in pregnant and postpartum women, and in men with severe liver disease. The absence of evidence of o t h e r disorders associated with intimal proliferation suggested its relation to endogenous and exogenous steroids. Tile final vascular compromise may be due to either severe narrowing by the intimal proliferation or a combination of that lesion with a thrombopathic state. Blaustein et al.4'5 had reported earlier regarding smooth muscle and endothelial proliferation in spiral arterioles deep in the endometrium of women taking contraceptives orally, and the possibility exists tlmt such changes are of a similar o r d e r of response. But the literature on this point remains sparse and no effort seems to have been made to investigate the nature of the vascular lesion by controlled studies in primates. Endometrium The endometrial changes associated with oral contraception vary with the time during tile treatment cycle at which a specimen is taken for histopathologic
EFFECTS OF CONTRACEI'TIVES ON T H E UTERUS--OnER stttdy as well as with the a m o t m t o f progestagen in the tablet. I'erhaps tire simplest approacit to the subject is historical. O n e o f the first "pills" to become available was Enovid, 10 nag., containing 9.85 rag. o f n o r e t h y n o d r e l and 0.15 mg. o f ethinyl estradiol, a strongly progestational formulation. A 21 year old woman who had undergone bilateral o6phorectomy four years previously desired to resume cyclical menstruation. A pretreatment biopsy disclosed an inert endometrium (Fig. 1). The endometrium was primed for three weeks with oral doses of stilbestrol, 1.25 rag. daily, which was tlten discontinued, with resultant withdrawal bleeding. On the fifth day after the bleeding began she received Enovid, 10 nag., for 20 days. On tire twenty-fifth day anotlter endometrial biopsy revealed small tubular glands, but the epithelium was somewltat lower than in the pretreatment specimen, indicating tlmt it migltt ltave gone through a secretory cycle (Fig. 2). The stroma showed a diffuse decidualike transformation. Spiral arterioles were not in evidence, but the endometrial venules were moderately dilated.
In ovttlating w o m e n studied subsequently it soon b e c a m e evident that tiffs basic pattern o f response to the c o m b i n e d r e g i m e n was fairly c o n s t a n t : At the end o f 20 days o f treatment, the a p p e a r a n c e o f the e n d o m e t r i u m gave rise to the term suppressed e n d o m e t r i t n n . T h e intensity o f the stromal decidual change varied widely f r o m patient to patient, but it was rarely absent at tire 10 mg. dose level. In some e n d o m e t r i a it was weak or sparse, but in tlte majority it was m o d e r a t e to strong. T h e d e g r e e o f dilatation o f venules also varied, being absent in about ltalf the specimens examined. By taking aspiration biopsy specimens at various stages in the t r e a t m e n t cycle, it was soon established that the endometrial glands did go t h r o u g h a secretory cycle3 Specimens obtained on cycle days 9 to 12 showed p r o m i n e n t subnuclear and s u p r a n u c l e a r secretory vacuoles, resembling those seen in the normal e n d o m e t r i u m o f ovulating w o m e n on cycle days 16 to 18. This p l t e n o m e n o n , labeled precocious secretion, was clearly the effect o f admin-
Figure 1 Figure 1. Inert endometriunl from 21 )-ear okl castrate.
Figure 2
Figure 2. Entlomeniunl after estrogen printing, withdrawal bleeding, and Enovid for 20 days. Note secretory exhaustion of glands, a decidua-like stromal change, dilated venules, and absence of spiral arterioles.
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istering a progestagen with an estrogen. Biopsy specimens taken later in the treatment cycle showed progressive regression of tlm precocious secretory reaction until hyperinvolution was seen circa day 20. Decidna-like stromal reactions were seen as earl)' as day 17, but spiral arterioles never sprouted toward tim surface epithelium. Subsequent formulations o f tlm combined "pill" reduced tim a m o u n t of progestagen needed to inhibit tlm pituitary gonadotropins and ovulation to the 5 rag. level, at wlfich point decidua-like stromal reactions became weak and infrequent. Still later formulations reduced tim a m o u n t of progestagen to 2.5 or even 2.0 rag., which was sufficient to inhibit ovulation. Tile clinical advantage of tiffs manipulation of dosage was to reduce "breakthrougll bleeding," an undesirable side effect (q.v.). At tiffs dose level there e m e r g e d tim picture of small endometrial glands lined by low epithelium without mitoses or secretion a n d e m b e d d e d in a loosely reticular, naked nucleus stroma; a decidua-like stromal reaction was extremely u n c o m m o n and no development of spiral arterioles or dilatation of venules occurred (Fig. 3). Tim use of sequential regimens supplied a somewhat opposite picture in the endometrium. During tim first 15 or 16 days of tim treatment cycle, tim patient received small doses of estrogen, either ethinyl estradiol or its 3-methyl ether, mestranol. Bioptic material taken d u r i n g tiffs plmse of the cycle showed only an estrogenic effect, i.e., tubular glands with increased mitotic activity but no secretion. Tim stroma was compact and of the naked nucleus type. Witlfin 48 hours after tim progestagen containing pill was added to the regimen, subnuclear and supranuclear secretory vacuoles appeared. Tiffs phen o m e n o n was labeled retarded secretion because it resembled tim normal pattern in ovulating subjects on days 16 to 18 but appeared in treated subjec{s on days 22 to 25. This secretory plmse was short lived, and regressive changes soon appeared. A weak decidua-like stromal transformation appeared circa days 24 to 25, but tim spiral arterioles remained suppressed. 8 Both tim combined and the sequential
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.,
Figure 3. Endometrium after Norgestrel, 0.5 nag., plus ethylestradiol, 0.05 mg., for 20 days. Note small tubular glands with no mitoses or secretion, loose reticular stronm with no predecidua, and no dilatation of venules or spiral arteriolar developme,m liner, Higher power view.
regimens are discontinuous, with tile medication stopped to permit cyclical withdrawal bleeding on schedule. Tile regimen for treating endometriosis differs in that it is continuous, with increments of the daily dosage of progestagenestrogen up to 30 mg. Withdrawal bleeding wonld be undesirable in patients with endometriosis because bleeding would also occur into tile pelvic tissues, producing the characteristic pain that the treatment was designed to abolish. Samples of endometrium taken at this high dosage level exlfibit a diffuse, intense decidual reaction that resembles that of decidua in tim first and second trimesters of pregnancy. Tim decidual cells are arranged in a pavement pattern, and tim glands are reduced to slitlike lumina, easily mistaken for small blood vessels (Fig. 4). Other regimens Imve been tried for
EFFECTS OF CONTRACEPTIVES ON T H E UTERUS-OBc~ for as long as one )'ear after the medication was stopped. T h e e n d o m e t r i u m after two o r t h r e e injections o f Depo-l'rovera was t h i n n e d and almost atrophic and was c o m p o s e d o f small h y p e r i n v o h l t e d glands in a compact, naked nucleus, stronta witltout vascular d e v e l o p m e n t (Fig. 6). T h e s e anatomic observations are based largely on material studied personall)', but tlte)" are in close a g r e e m e n t with those o f o t h e r reports. 'J-tt l'atterns Of endometrial response to oral adntinistration o f contraceptives tend to remain constant f r o m cycle to cycle over a period o f years) 2'~3 We have c o n f i r m e d this in o u r own studies o f biopsy specimens f r o m about 50 patients who were subjected to r e p e a t e d biopsy at intervals ranging f r o m one to 12 years while taking medication.Z4
Figure 4. Endometrium after six months of coqtixmous treatment with Enovid, 10 rag. daily, for endometriosis. Note intense decidual reaction and slitlike glands lined by flattened epithelium.
contraception but have p r o v e n unsatisfactory either because o f "breakthrougi~ bleeding," "postpill a n l e n o r r h e a , " or both. For example, a low dosage schedule o f Norgestrel, a potent progestational agent, given at a level o f 0.5 mg. daily and continuously, inlfibited ovulation, but breaktin'ough bleeding was a significant contplication. Endometrial biopsy after a few weeks o f medication showed small tubular glands lined by low epitllelium and an intense decidual reaction in tlte stroma witltout the d e v e l o p m e n t o f spiral arterioles (Fig. 5); dilatation o f venules was not a p r o n t i n e n t feature. Depo-Provera, administered intramuscularly at a level o f I00 rag. every three weeks or 200 mg. every six weeks, also inltibited ovulation, but a r e t u r n to cyclical menses was u n p r e dictable, and a m e n o r r h e a could persist
Figure 5. Endometrimn after low close Notgestrel nsed continuously. Note intense decidual reaction and glands lined by flat epitheliunl. Spiral arterioles are inhibited.
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Figure 7. E n d o m e t r i u m at the time o f " b r e a k t h r o u g h bleeding." Note laminated t h r o m b u s attached b)" a small base to the endothelium o f a dilated VCI|IIIC.
Figure 6. E n d o m e t r i u m after four injections o f Depo-Provera, 200 rag., at three m o n t h intervals. Glands are r e d u c e d to slits, and the entire mucosa is thinned. A weak predccidual reaction is present in the stroma, but spiral arterioles are not developed.
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One problem of interest is tile anatomic basis for "breaktln'ougll bleeding," i.e., unexpected bleeding during a treatment cycle. Most specimens taken shortly after the onset of bleeding reveal only hemorrhagic material, fragments of autolyzed endometrium, and debris. Occasionally a recent laminated thrombus is seen in a dilated venule within the superficial endometrium (Fig. 7). Tile thrombus seems to be atta~2hed by a snmll base mttch like those described by Irey et al.2"3 in larger vessels. The dilated venule also bears some resemblance to those so commonly found in hyperplastic endometria, and it is tempting to ascribe 9dilatation of the venules in women using contraceptives orally to the estrogen component of the pill. Some reinforcement of
this idea is supplied by collateral evidence in a study of quinestrol, a synthetic estrogen with no progestational properties. 15 In an occasional biopsy specimen obtained after a few months of medicaion, thrombosis and infarction have been seen in tile endometrium (Fig. 8), but there is good reason to believe tlmt in women receiving contraceptives orally the progestagen modifies tile response. Occasionally the pathologist may be confronted by an endometrial biopsy specimen from a patient with "postpill amenorrbea." The majority of women with tlfis complication probably did not have regular ovulatory cycles before orally effective contraceptives were prescribed, and such endocrinologic evidence as exists indicates a disturbance in the hypothalamus-pituitary axis. Usually tile pathologist is merely able to confirm by his examination of the endometrium that the patient is not ovulating, but occasionally he may detect weak or early evidence of secretory activity and issue an encouraging report. An early report by Dockerty et al. TM called attention to an unusual degree of
EFFECTS OF C O N T R A C E I ' T I V E S ON T H E U T E R U S - O B E R
Figure 8. Endometrium after quinestrol. Note mild glandular hyperplasia and marked dilatation of venules with thrombosis and local infarction.
e n d o m e t r i a l s t r o m a l p r o l i f e r a t i o n , labeled "pseudomalignant," in three women receiving p r o l o n g e d u n i n t e r r u p t e d p r o gestagen-estrogen medication. In rare instances atypical cells c a n be f o u n d in the e n d o m e t r i a l s t r o m a o f patients r e c e i v i n g c o n t r a c e p t i v e steroids, b u t s u c h cells a r e clearly b i z a r r e w i t h o u t a neoplastic c o n n o t a t i o n (Fig. 9).*
Cervical Glandular Epithelium U n l i k e the relatively u n i f o r m a n d p r e d i c t a b l e r e s p o n s e o f tile e n d o m e t r i u m , the e n d o c e r v i x reacts to c o n t r a c e p t i v e
*Editor's note: A role of oral administCation of contraceptive medication, specifically of the sequential type, in the development of endometrial carcinoma in young women has been suggested by the recent reports of Silverberg and Makowskit7 and Kaufman et al.,TM but the question of overdiagnosis of atypical growth patterns associated with estrogenic stimulation must be raised in cases of this type. This subject is discussed further in the Current Topic, "Estrogens and Endometrial Carcinoma," elsewhere in this issue.
Figure 9. Endometrium after Ortho-Novum. Note stromal cells with large, bizarre, hyperchrontatic nuclei. Inset, at higher magnification, reveals smudgy nature of nuclear material. Mitotic figures were absent.
steroids in a facultative way, a n d in m o s t instances tile histopatllologic c h a n g e s a r e unimportant. The endocrine milieu' c r e a t e d by tile ingestion o f a synthetic progestagen-estrogen is o f t e n t e r m e d " p s e u d o p r e g n a n c y , " a n d as in t r u e p r e g n a n c y o n e can o f t e n d e m o n s t r a t e an i n c r e a s e d h e i g h t o f the e n d o c e r v i c a l ceils and some degree of hypersecretion. T i l e i m p o r t a n t e n d o c e r v i c a l lesion was first d e s c r i b e d in 1967 by T a y l o r , I r e y , a n d N o r r i s , 19 w h o identified a distinctive atypical g l a n d u l a r p r o l i f e r a t i o n in 13 w o m e n r e c e i v i n g c o n t r a c e p t i v e s orally. T h e lesion was p o l y p o i d in m o s t o f tile cases. A m a j o r i t y o f tile patients w e r e asymptomatic, but some complained of postcoital o r i n t e r m e n s t r u a l spotting. T h e a u t h o r s e m p h a s i z e d the i m p o r t a n c e o f
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recognizing the benign nature o f the lesion. C a n d y and Abell z~ r e p o r t e d ano t h e r 12 examples; most o f their patients had polypoid or friable papillary lesions at o r p r o t r u d i n g f r o m the cervical os. Using the term microglandular hyperplasia, Kyriakos et al. 2~ r e p o r t e d 30 cases; three o f their patients were p r e g n a n t at the time o f biopsy, but one was neither p r e g n a n t n o r taking steroids orally. Govan et al. 2z r e c o r d e d 15 additional examples, 10 in contraceptors and five in p r e g n a n t women. T h e s e observers astutely pointed out that the lesion was cytoplasmic r a t h e r than nuclear and that it seemed to occur in pre-existing polypoid endocervical lesions m which reserve cell hyperplasia was already present. Nichols and Fidler e3 reviewed 128 consecutive cone biopsy specimens o f the cervix and f o t m d microglandular hyperplasia in 31 o f t h e m (24 per cent). Twentytwo o f the women (71 p e r cent) were using contraceptive steroids, but t h r e e w e r e p r e g n a n t and five who were not using contraceptives orally at the time o f biopsy
had nsed t h e m within the previous )'ear. Many o f the lesions in tiffs series were snmll and were detected only because n u m e r o u s sections were made o f the specimen. In some instances multiple small discrete loci were scattered at r a n d o m in the endocervical mucosa. T h e authors advanced the hypothesis that a progestagen was necessary for the lesion to develop but not necessary for its support. T h e morphologic features o f microglandular hyperplasia, w h e t h e r polypoid or not, consist o f a h o n e y c o m b or cribrif o r m mass o f tightly packed acini, varying somewhat in size and shape but mostly irregular. T h e glands are lined by a low cuboidal to flattened single layer o f nlucns secreting epitheliun~ and do not seem to be invested with basement m e m b r a n e like normal endocervical glands. T h e r e is little variation in nuclear size, shape, or staining properties, and mitotic figures are sparse (Figs. 10, 11). In polypoid excrescences the impression is one o f a syncytial o u t g r o w t h f r o m a mildly inflamed base. Leukocyte infiltration is
Figure I0. l.ow power view of polypoid excrescence of endocervix after 20 cycles of Enovid, 5 rag. 9 Note the lacy pattern of microglandular hypcrplasia.
Figure 11. Higher magqification of Figure 10. Note closely packed glands lined by uniform cuboidal cells with vesicular nuclei. The glands contain nltlctls. but mitosesare not seen. A normal endocervical gland is included for comparison.
EFFECTS OF CONTRACEPTIVES ON THE UTERUS-OnER COllllnon; if ulceration is present, neutrophils predominate, but in intact lesions plasma cells and eosinophils are often abundant. Czernobilsky et ai.2~ have reported a single case o f papillary adenocarcinoma of the endocervix in a 25 )'ear old woman who had been receiving combined-regimen contraceptives orally (ethynodiol diacetate and mestranol) for f o u r )'ears. Presumably this was a coincidental association, but pathologists should be on guard for f u t u r e anecdotal material of this nature.
CervicalSquamous Epithelium T h e squamous epithelium is even less prominent a target for synthetic steroids than the glandular epithelium. A n u m b e r of pertinent histopathologic or cytopathologic studies have been carried out, and discrepancies exist. Some of the confilsion can be traced to differences of interpretation, but some is also due to the types o f populations investigated. A combined cytologic and histologic study o f over I00 randontly selected patients u n d e r the age of 50 )'ears receiving contraceptives orally at the family planning clinic o f an arm)' hospital failed to disclose significant lesions, t h o u g h minor aherations a b o u n d e d in the biopsy specimens. 25 A colposcopically guided study of cervical biopsy specimens taken both before and after medication in 58 muhiparous Mexican women with a mean age of 30+ years revealed no precancerous lesions. ~6 Perhaps the most reassuring report is the retrospective study of 196 women with invasive cervical cancer who exhibited no difference in their oral use of contraceptives fi'om that of a carefully selected set of controls matched for age, ethnic background, age at first coitus, age at first pregnancy, n u m b e r of pregnancies, and socioecononfic status. 27 Another retrospective study based on 324 wonten with cytologic smears suggestive o f neoplasia, matched with 302 controls, led to the conclusion that those women using contraceptives orally for a mean tSeriod of 20 months were no more likely to have squamous metaplasia or carcinoma in situ within two and one-half
to three years after tile initiation of therapy than women who did not use contraceptives orally. 2s Tile limitation of this study lies in the short interval of observation; one would expect a longer latent period for carcinogenesis related to hormones. An extensive study by Melamed et al.29 compared the exfoliative cytology in 27,500 women using steroids orally for contraception with that in 6800 women using the diaphragm. T h e statistical complexities are formidable, but the authors concluded that there was a small but statistically significant increase in the prevalence rate of carcinoma in situ a m o n g the women choosing and using orally effective steroids. Tlle authors caution that this increase call be attributed either to a decreased prevalence rate a m o n g women using the d i a p h r a g m or to an increased rate a m o n g those using orally effective steroids; the reason for tlle difference was not apparent fi'om their data. In a later study fi'om tile same clinic the authors reported an incidence rate of biopsy proven carcinonta ill situ of 2.3 in steroid users compared with 1,4 in diap h r a g m users, and 1,4 ill steroid users compared with 0.6 in women using an intrauterine device, a9 Tile numerical values indicate that the use of a barrier type o f contraceptive, i.e., the diaphragm, may not be quite so effective a protection against transformation of the squamous epithelium as formerly imagined, but the influence of motivational factors in selecting tile method for contraception cannot be excluded. Lacking in this and similar studies is an account o f the sexual activity of the women at risk, especially those in tile y o u n g e r age groups with early and frequent coital exposures to an assortment o f male partners. T h e cervix was not designed by nature as a trampoline, and sexual activity rather than oral steroid medication or ahernative methods for contraception may be decisive. T h a t the prevalence rates given by Melamed et al. are higher than in .other clinics has been noted by m a n y and is often attributed to origfin fi'om a l'lanned P a r e n t h o o d population in New York with all the innuendoes about the mores of that " f u n city." But the study by Kline
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HUMAN PATHOLOGY--VOLUME 8, NUMBER 5 September1977 et al.3t from Boston indicates a 2.0 per cent rate of abnormality in both squamous and endocervical cells in a population of 2300 women receiving contraceptive steroids, contrasted with a 1.0 per cent rate in over 17,000 women not receiving steroids. Lacking in both studies is an}' comment regarding the fi'equency of the "atypia of pregnancy," a reversible cytologic finding that can readily be accounted for by tile state of pseudopregnancy induced by the progestagen-estrogen preparation. In a sense Doughert} a2 supports the numerical values of Kline et al., having found twice the expected rate of cytologic atypia ill a continuous study of repeated smears from ahnost 2000 women receiving sequential steroid contraceptive medication in a Louisiana clinic. A prospective study by Stern et al? 3 fi-om Los Angeles found "dysplasia" in 9.0 per cent of tile cytologic smears in pill users, 5.3 per cent in intrauterine device users, and 3.7 per cent in diaphragm users. These numerical vahles support tile idea that a barrier contraceptive does protect tile cervical squamous epithelium fi'om atypical cellular changes, and the authors relate their findings to factors in the decision making ln'OCeSS at the time of contraceptive counseling. It is ditlicuh for a lfistopathologist to evaluate a report of tiffs nature, whicll is not supported by biopsy material and accepts "dysplasia" as an index of carcinogenic potential without a description or qualification of the term. The study by Worth and Boyesa~ from British Columbia was based on "preclinical carcinoma," another term tlmt is difficult to define with precision. Analyzing 310 cases so diagnosed, matched with 682 controls, they fotmd no difference in contraceptive usage, but they did find an increased frequency in the women with preclinical carcinoma in abnormal marital situations, including mtditple marriages, divorces, and common-law relationships. These women also had a higller preguancy rate and parity than the controls, and their age at first pregnancy was younger and antedated the age at marriage-suggesting, as the authors politely phrased it, "a different pattern of belmviour in the two groups." The most recent stud}' of importance
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to deal with this question is by Dabacens et al. z5 fi'om Santiago, Chile, who compared 2400 women using an intrauterine device for 3200 woman-years with almost 2700 women using long acting injectable progestagens (chlormadinone acetate and medroxyprogesterone acetate) for over 7000 woman-years. The subjects were studied by repeated cytologic examinations, colpomicroscopy, and punch biopsy or cone biopsy as indicated. The authors concluded that tile incidence rate of new lesions appearing during the use of these contraceptive methods was the same for both groups. Despite the unresolved differences of opinion, it is reasonable to quote the conclusions from Dougherty's article? 5 1. The pills do not protect against cancer. 2. The pills do not cause cancer in the generally accepted meaning of this stateInent.
Myometrium Attention was directed to the effects of steroid induced pseudopregnancy oil the myometrium quite early when Andrews et al. 36 reported progressive enlargement of uterine leiomyomas in seven women being treated with continuous progestagen-estrogen medication for peh, ic endometriosis. Three of these women required hysterectomy, and microscopic examination of their leiomyomas showed "typical pregnancy hypertrophy." Tile tumors in the remaining four patients returned to their original size after the medication was stopped. A case of acute hemorrhagic degeneration of a leiomyoma was reported by Briscoe, a7 but the patient had received Norlutate, 5 rag., for only three days before "bursting" suprapubic pain was reported. One suspects tlmt circulation to the pre-existing leiomyoma was already compromised before the medication was started. On microscopic examination tile tumor was celhdar and actively growing; extensive edema separated individual smooth muscle cells and bundles, and there was pronounced dilatation of engorged veins with irregular zones of hemorrlmge as well as foci of acute necrosis. Because of reports like these, the
EFFECTS OF CONTRACEPTIVES ON THE UTERUS--OgER presence of palpable leiomyomas was generally considered a contraindication to prescribing contraceptive steroids. Prakash and Scullyas reported a case in which Norethindrone, administered in dosages ranging from 30 to 60 mg. daily for 14 months, produced progressive enlargement of a uterine leiomyoma. In addition to hypercellularity, edema, and foci of necrosis,.the tumor contained cells with large bizarre layperchromatic nuclei resembling those seen in leiomyosarcomas so closely that tim authors labeled the changes "sarcoma-like" and cautioned against overinterpretation of such responses. In tiffs striking case the medication used contained no added syn-
thetic estrogen, though contamination with traces of estrogen in its manufacture could not be exch, ded. The implication was that the accelerated growth response and atypia could be purely a progestational effect. Later Fechner a9 reviewed the problem and added five cases of Iris own. In addition to large irregular hyperchromatic nuclei he illustrated cases in wlfich the nuclei were multilobated. It is sometimes difficult to judge whether in some specimens there may not be multiple nuclei forming a plasmodium-like syncytlunl (Fig. 12). Mitotic figures, which are the best index of malignancy in cellular smooth muscle tumors, are usually present in slightly increased numbers, but a true leiomyosarcoma in a patient receiving contraceptive steroids has yet to be reported. In examining routine sections for mitotic activity, it is extremely important not to include pyknotic nuclei whose crenated borders may suggest nuclei in anaphase. EFFECTS OF I N T R A U T E R I N E DEVICES
Figure 12. Uterineleiomyomagrowingrapidly in womantakingcontraceptivesorally.Noteincreased celh,larity with many large h)'perchronmtic nuclei.. Inset, Higher magnificationshowing muhinudeated smooth musclesyncytia.
Grtifenberg's silver ring was tile first usable intrauterine contraceptive device of the modern era. Developed in tile 1920's, it had only limited application and fell into desuetude for a number of reasons but was recalled to memory when devices made from molded polyethylene plastic or from metal began to compete with synthetic steroids. Tile convenience of a contraceptive method that requires only a single insertion is self-evident. There has been considerable debate about tile mechanism whereby intrauterine devices prevent pregnancy. Animal experiments have indicated considerable species variation in the contraceptive mechanism of polyethylene devices. The consensus is that a mild nonbacterial intlammatory response is in some way involved. Electron microscopic studies have shown platelet-like thrombi in endometrial capillaries, damage to the surface epithelium near contact points, and asynchronous premature maturation of the endometrium. ~~ But tim frequent observa-
523
HUMAN PATHOI.OGV--VOLUME 8, NUMBER 5 September 1977 tion o f an e x u d a t i o n o f p o l y m o r p l m n u clear lenkocytes c a n n o t be discounted. 4 Col)per bearing devices also elicit a polym o r p h o n u c l e a r e x u d a t i o n , but in addition the cupric ion inhibits several e n z y m e systems?" Inhibition o f alpha-amylase interferes with the n o r m a l cyclical increase in glycogen, and inhibition o f carbonic a n h y d r a s e can lead to a local increase in bicarbonate ion; perhaps failure o f both these enzyme systems creates an unfavorable tissue milieu for nidation. Inevitably insertion o f a device t h r o u g h the endocervical canal will introduce bacteria into the cavum uteri. Tim early study by Misheli et al. 4a d e m o n strated that the u t e r u s sterilizes itself from such contaminants after a month. Presumably most o f tim bacteria are not patlmgenic. But in a certain p r o p o r t i o n o f device users, e n d o m e t r i a l inflammation develops, p r o d u c i n g bleeding, vaginal discharge, and peh'ic pain. O b e r et al. 4~'4~ r e p o r t e d a 25 per cent fi'equeqcy o f significant endometritis in syml)tomatic polyethylene device users a n d d e m o n s t r a t e d that this rose to a 40 p e r cent level as the time o f e x p o s u r e was p r o l o n g e d to m o r e than three years. Squamous metaplasia o f the e n d o n m t r i u m was f o u n d in several cases and occasionally foreign body giant cells were e n c o u n t e r e d (Fig. 13). Intlammatory reactions of the e n d o m e t r i u m are only slightly less fi-equent in association widl c o p p e r b e a r i n g devices; a c o m m o n pattern is the presence o f I m l y m o r p h o n u clear leukocytes in glandular hnnina with a thin layer o f e x u d a t e on tim surface but without leukocytic infiltration o f tim stroma (Fig. 14). T w o specific incidents r e g a r d i n g endometritis associated with intrauterine devices merit citation. T h e Majzlin spring p r o d u c e d severe intense endometritis in m a n y patients within a few months o f insertion, a6 T i m spring was m a n u f a c t u r e d f r o m stainless steel that contained about 18 per cent chronfiuna and 9 per cent nickel in the alloy; both these metallic runs are highly irritating to mucosal surfaces. T h e Dalkon shield, m a n u f a c t u r e d from ethylvinyl acetate i m p r e g n a t e d with c o p p e r sulfate and metallic copper, was associated with 209 septic midtrimester abortions and 11 maternal deaths. T a t u m
524
Figure 13. Endometrium following t,se of intrat*terme contraceptive device. Note squamous metaplaskl of stirface with basal cell hyl)eqflasia .rod chronic inIkunmation in the sub.jacen~ mucosa. (PA5 stain.) et al. 47 f o u n d that although the tail o f most o t h e r devices was a single or double monofilament thread, the tail for the Dalkon shield was c o m p o s e d o f either 400 (standard size) or 200 (small size) filaments in a plastic sheath. T h e wicklike action o f tile tail p e r m i t t e d fluid and bacteria to ascend f r o m tile vagina into the uterine cavity. Electron micrographs have revealed bacteria in tim interstices between tim filam e n t s . A c o m p a r a b l e tail was used o n the Majzlin spring. Both devices lmve been withdrawn by the nmnufacturer. Unless pelvic infection develops or p r e g n a n c y supervenes, the endometritis associated with intrauterine devices is usually self-limited. Even wllen biopsy has shown chronic productive endometritis at the time o f removal, rebiopsy after two or t h r e e cycles without the device shows that the inflammation has disappeared. At such time it may be a p p r o p r i a t e to insert a fl'esh device if c o n t i n u e d contraception by tlmt m e t h o d is desired. It is difficult to calculate the role o f intrauterine devices in relation to tile incidence o f saipingitis, salpingo-o6phoritis,
EFFECTS OF CONTRACEPTIVES ON THE UTERUS--OBER
Figure 14. Endometrium following use of intrauterine contraceptive device (copper T). Note glandular lumina filled with polymorphonuclear leukocytes exuding to form a catarrhal membrane on the surface. T h e r e is no leukocytic reaction in the endonletrial stroma.
an antigonococcal effect, no one has suggested that it is prophylactic against infection by that organism. Needless to say, pathogenic micro-organisms recovered from clinical cases of pelvic infection show diversity and heterogeneity of species. Another potential complication of intrauterine devices is ectopic pregnancy. Recent data indicate that in copper T users, 3,4 per cent of pregnancies are extrauterine, a value higher titan that usually given for the general population. ~ There is no doubt that accidental pregnancy in a device user (method failure) does carry a high risk of complication. Excluding the 55 to 60 per cent of women who elect abortion, about 15 have a spontaneous abortion and only 20 per cent lmve a live birth. Even more dangerous than pelvic infection or accidents of pregnancy are the occasional examples of intestinal obstruction tlmt occurs when an intrauterine device perforates the uterus and becomes entangled with omentum and loops of bowel. Given a large enough volume of material, pathologists can expect to see all the complications enumerated.
ACKNO~,VLEDGblENTS
tubo-ovarian abscess, and other forms of pelvic inflammatory disease. Far too many uncontrolled variables combine to make analysis of data treacherous. In the best controlled study by Mead et al.,4s-41 per cent of all women admitted with acute pelvic infection wore intrauterine devices, and presumably this is a higher figure than tim percentage of device users in the general p o p u l a t i o n - b u t the latter number cannot be determined. Further, over half the patients with pelvic sepsis were using either the Dalkon shield or the Majzlin spring; presumably other devices are safer. Nine cases of septic abortion occurred, all in Dalkon shield wearers. Only two cases yielded isolates of N. gonorrheae. But it is difficult to be certain whether the risk of pelvic infection should be assigned to tim device or to promiscuity. Altlmugll tim cupric iota has
From 1960 to 1973 I had tim pleasure and privilege of serving as consulting pathologist at tile Margaret Sanger Research Bureau and from 1961 to 1972 at the New York Fertility Institute. During this period many of the drugs and devices now used for contraception were being tried and tested. To collaborate with my clinical colleagues in this work was a challenge and a rewarding experience. No bistopathologist can reach beyond tile material given him by his clinical associates nor is he likely to provide answers to questions they do not put. It was also my pleasure to share this unique pathological material, which I had in such abundance, with my fellow pathologists in a series of articles dating from that period, i must acknowledge the generous and friendly cooperation of Doctors Aquiles J. Sobrero and Jeaane C. Epstein of tim Margaret Sanger Research Bureau and of Doctors
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8, N U M B E R 5
M a r t i n J. C l y m a n a n d M a x w e l l R o l a n d o f t h e N e w Y o r k F e r t i l i t y I n s t i t t t t e . B u t this e s s a y is d e d i c a t e d to t h e m e m o r y o f t h e late D o c t o r s L e n a L e v i n e a n d M i l d r e d E. W a r d of the Bureau, two compassionate gTnecoiogists whose idealism informed their c l i n i c a l skills a n d w h o i n s p i r e d u s all.
REFERENCES !. FDA Drug Bulletin, 6:26-27, 1976. 2. Ire)', N. S., Manion, W. C., and Taylor, ti. B.: Vascular lesions in women taking oral contraceptives. Arch. Path., 89:1-8, 1970. 3. Irey, N. S., and Norris, tt. J.: Intimal vascular lesions associated with female reproductive steroids. Arch. Path., 96:227-234, 1973. -4. Blaustein, A., Shenker, L., and Post, R. C.: The effects of oral contraceptive on the endometrium. Internat. J. Fertil., 13:466-474, 1968. 5. Blaustein, A., and Shenker, L.: Responsiveness of endothelium in spiral arterioles of endometrium. Obst. Gynec., 35:12-20, 1970. 6. Ober, W. B.: Synthetic progestagen-oestrogen preparations and endometrial morphology. J. Clin. Path., 19:138-147, 1966. 7. Roland, M., Clyman, M.J., Decker, A., and Ober, W. B.: Sequential eudometrial alterations during one cycle of treattnent with synthetic progestagen-estrogen compounds. Fertil. Steril., 17:338-350, 1966. 8. Ober, W. B., Decker, A., Clyman, M.J., and Roland, M.: Endometrial morpholo~" after sequential medication with mestranol and chlormadinone. Obst. Gynec., 28:247-253, 1966. 9. Martinez-Manautou, J. M., Maqueo, M., Gilbert, R. A., and Goldzieher, J. w.: Human endoinertial activity of several new derivatives of 17-acetoxyprogesterone. Fertil. Steril., 13:169183, 1962. 10. Maqueo, M., l'erez-Vega, E., Goldzieher, J. W., Martiuez-Manautou, J. M., and Rudel, H.: Comparisou of the endometrial activity of 3 synthetic progestius used in fertility control. Am. J. Obst. Gynec., 85:427-432, 1963. 11. Maqueo, M., Becerra, C., Munguia, H. and Goldzieher, J. W.: Endometrial histology and vaginal cytology during oral contraception with sequential estrogen and progestin. Am. J. Obst. Gynec., 90:395-400, 1964. 12. Rice-Wray, E., Aranda-Rosell, A., Maqueo, M., and Goldzieher, J. W.: Comparison of the longterm endometrial effects of synthetic progestins used in fertility control. Am. J. Obst. Gynec.,87"429-433, 1963. 13. Ryan, G. M., Craig, J., and Reid, D. E.: Histolo~of the uterus and ovaries after long-term cyclic norethyuodrel therapy. Am. J. Obst. Gynec., 90:715-725, 1964. 14. Ober, W. B.: Unpublished data. 15. Ober, W. B., and Bronstein, S. B.: Endometrial morphology following oral administration of
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17.
18.
19.
20. 21.
22.
23.
24.
25.
26.
27. 28. 29.
30.
31.
September 1977
quinestrol. Internat. J. Fertil., 12:210-228, 1967. Dockerty, M. B., Smith, R. A., and S)mmonds, R. E.: l'seudomalignant endometrial changes induced by administration of new synthetic progestins. Proc. Staff Meet. Mayo Clin., 34: 321-328, 1959. Silverberg, S. G., and Makowski, E. L.: Endometrial carcinoma in young women taking oral contraceptive agents. Obst. Gynec., 46:503506, 1975. Kaufman, R. [I., Reeves, K. O., and Dot,gherty, C. M.: Severe atypical endometrial changesand sequential contraceptive use. J.A.M.A., 236: 923-926, 1976. Taylor, H. B., Irey, N. S., and Norris, H. J.: Atypical endocervical h)'perplasia in women taking oral contraceptives. J.A.M.A., 202: 637-639, 1967. Candy, J., and AbeIl, M. R.: Progestogen-induced adenomatous hyperplasia of the uterine cervix. J.A.M.A.,203:323-326, 1968. Kyriakos, M., Kempson, R. I., and Konikov, N. F.: A clinical and pathologic study of endocervical lesions associated with oral contraceptives. Cancer, 22:99-110, 1968. Govan, A. D. T., Black, W. P., and Sharp, J. L.: Aberrant glandular polypi of the uterine cervix associated with contraceptive pills: pathology and pathogenesis. J. Clin. Path., 22:84-89, 1969. Nichols, T. M., and Fidler, H. K.: Microglandular Iwperplasia in cervical cone biopsies taken for SUSl~icious and positive cytology. Am. J. Clin. Path., 56"424-429, ! 97 i. Czernobilsky, B., Kessler, I., and Lancet, M.: Cervical adenocarcinoma in a woman on longterm contraceptives. Obst. Gynec.,43:517-52 I, 1974. Gall, S. A., Bourgeois, C. t!., and Maguire, R.: The morphologic effects of oral contraceptive agents on the cervix.J.A.M.A., 207:2243-2247, 1969. Carbia, E., Rubio-lSnares, G., Alvarado-Duran, A., and Lopez-Llera, M.: Histologic study of the uterine cervix during oral contraception with ethynodiol diacetate and mestranol. Obst. Gynec.,35:381-388, 1969. Boyce,J. G., Ln, T., Nclson,J. H., andJoyce, D.: Cervical carcinoma and oral contraception. Obst. Gyncc.,40:139-146, 1972. Thomas, D. B.: Relationship of oral contraceptives to cervical carcinogeqesis. Obst. Gynec., 40:508-518, 1972. Melamed, M. R., Koss, L. G., Flehinger, B. J., Kelisky, R. P., and Dubrow, H.: Prevalence rates of uterine cervical carcinoma in situ for women using the diaphragm or contraceptive oral steroids. Brit. Med. J., 3:195-200, 1969. Melamed, M. R., and Flehinger, B. J.: Early incklence rates of precancerous cervical lesions in women using contraceptives. Gynec. Oncol., 1:290-298, 1973. Kliue, T. S., Holland, M., and Wemple, D.: Atypical cytology with contraceptive hormone medication. Am. J. Clin. Path., 53:215-222, 1970.
EFFECTS OF CONTRACEI'TIVES 32. Doughert)', C. M.: Cervical cytology and sequential birth control pills. Obst. Gynec., 36: 741-744, 1970. 33. Stern, E., Clark, V. A., and Coffelt, C. F.: Contraceptives and dysplasia: higher rate for pill choosers. Science, 169:497-498, 1970. 34. Worth, A. J., and Bo)'es, D. A.: A case control stud)" into the possible effects of birth control pills on pre-clinical carcinoma of the cervix. J. Obst. Gynaec. Brit. Comm., 79:673-679, 1972. 35. Dabacens, A., Prado, R. Larraguibel, R., and Zanartu, J.: Intraepithelial cervical neoplasia in women using i,atranterine devices and longacting injectable progestogens as contraceptives. Am. J. Obst. Gynec., 119:1052-1056,
42. 43.
44.
45.
1974.
36. Andrews, M. C., Andrews, W. C., and Strauss, A. F.: Effects of progestin-induced pseudopregnancy on endometriosis: clinical and microscopic stndies. Am. J. Obst. Gynec., 78: 776-785, 1959. 37. Briscoe, C. C.: Acute llcmorrhagic degeneration of.a leiomyonm following noretlfindrone acetate. Obst. Gynec.,23:279-280, 1964. 38. Prakash, S., and Scully, R. E.: Sarcoma-like pseudopregnancy changes in uterine leiomyonms. Obst. Gynec.,24:106-110, 1964. 39. Feclmer, R. E.: Atypical leiomyomas and s)'nthetic progestin therapy. Am. J. Clin. l'ath., 49:697-703, 1968. 40~ Wynn, R. M., and Sawaragi, 1.: Effects of intrauterine and oral contraceptives on the uhrastructnre of the human endnmctrium. J. Reprod. Fert. Suppl., 8:-t5-57, 1969. 41. Ancla, M., De Brux, J., antl Sinlon, I'.: Aneurysreal microthrombosis associated with intranter-
46.
47.
48.
49.
ON THE
UTERUS--OBrR
ine devices in the huma,i endometrinm. Lab. Invest., 17:61-70, 1967. Oster, G., and Salgo, 31. P.: The copper intrauterine device and its mode of action. New Eng. J. Med., 293"432-438, 1975. Mishell, D. R., Bell, J. M., Good, R. C., and Moyer, D. L.: Tile intrauterine device: a bacteriologic study of the uterine cavity. Am. J. Obst. Gynec., 96:i 19-126, 1966. Ober, W. B., Sobrero, A. J., Kurman, R., and Gold, S.: Endometrial morphology and polyethylene intrauterine devices. Obst. Gynec., 32:782-793, 1968. Ober, W. B., Sobrero, A. J., and Ctmbon, A. B.: Polyethylene intrat,terine contraceptive devices: endometrial changes following longterm use. J.A.M.A., 212:765-769, 1970. Ober, W. B., Sobrero, A. J., and Clmbon, A. B.: Endometrial findings after insertion of a stainless steel spring IUD. Obst. G)'nec., 36:62-68, 1970. Tatum, H. J., Schmidt, F. H., Phillips, D., *lcCarth)', M., and O'Leary, W. M.: The Dalkon shield controversy: structural and bacteriological studies of IUD tails. J.A.M.A., 231 : 711-717, 1975. Mead, P. B., Beecham, J. B., and Maeck, J. v. S.: Incidence of infection associated with the intrauterine contraceptive device in an isolated community. Am. J. Obst. Gynec., 125: 79-82, 1976. Tatum, tl. J., Schnfidt, F. It., and Jain, A. K.: Management and ontcome of preg,mncies associated with the copper T intrauterine contraceptive device. Am. J. Obst. Gynec., 126: 869-879, 1976.
10 Nathan D. l'erlman Place New York, New York 10003
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Abstract Combined regimen contraceptive steroids produce precocious endometrial secretion, followed by involution leading to a suppressed endometrium with small tubular glands and failure of spiral arterioles to develop; decidua-like stromal clmnges are dose related as is dilatation of venules. Thrombosis of the latter, perhaps estrogen mediated, leads to local tissue infarction and is the proximate cause of "breaktllrough bleeding." Sequential regimen contraceptive steroids lead to retarded endometrial secretion, failure of spiral arterioles to develop, and a weak decidua-like stromal transformation. Contraceptive steroids occasionally produce polypoid lesions of the endocervix with atypical microglandular hyperplasia. T h e r e are coriflicting reports about the effects of contraceptive steroids on the squanmus epitlmlium of the exocervix, but they neither protect against cancer nor cause it in the usually accepted sense. Uterine leiomyomas may exhibit increased cellularity and bizarre, hyperchromatic nuclei or mutinucleation in women receiving contraceptive steroids. Both polyethylene and metal-containing intrauterine devices may initiat(; inflamnmtory responses in tlm endometrium varying fi'om mild t o severe, related to tim time tim device Ims been in contact with the mucosa. Salpingitis and ectopic pregnancy are increased in frequency in device users.
Clinical trials of synthetic progestagens for contraception began in the late 1950's, and shortly thereafter polyethylene intrauterine devices were developed for the same purpose., By the end of the 1960's, a number of synthetic steroids, both estrogens and progestagens, were approved for both safety and efficacy. The ingenuity of physicians and
manufacturers combined to produce a wide variety of shapes and sizes of intrauterine devices made from either polyethylene or stainless steel, and in the 1970's copper became a prominent element in such devices. The social impact of relatively safe contraception was enormous, and sociologists and otlmr pundits spoke glibly of the "sexual revolution."
*l'mfcssor of l'athology, Mount Sinai School of Medicine of tile City Universityof New York. Attendingl'athologist,Beth Israel Hospital,New York, New York.
51 3
HUMAN PATHOLOGY--VOLUME 8, NUMBER 5 September 1977 Needless to say, one does not adntinister drugs on a continuing basis o1" insert a 9foreign body into the womb without incurring anatomical alterations, which are the subject of this essay. EFFECTS OF SYNTHETIC STEROIDS (ORALLY ADMINISTERED CONTRACEPTIVES)
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First, a word about orthography. Tile term progestogen was initially advanced to describe the class of synthetic steroids with progesterone-like activity. T h e suffix -ogen was used in conformity with its usage in such familiar terms as estrogen and androgen. But these are derived purely fiom Greek roots, whereas progesterone combines the Latin base gesta-, from gestate, to bear (a child), with the chemical suffix -one, which denotes a ketonic group in the molecule. Pro- and gesta- indicate something that promotes pregnancy or child bearing, and we speak of progesrational effects. The proper stem, therefore, is progesta-, to which tile suffix -gen may be added. T h e substances used in contraceptive "pills" are not naturally occurring hormones but products of the organic chemist's laboratory. Althougll their biologic properties are similar to those of endogenous estrogens and progesterone, neither their biologic nor morphologic responses are identical. Receptor sites sufficiently sensitive to discriminate between estradiol-17fl (active) and its stereoisomer, estradiol-17o~ (inactive), can also distinguish between the 19-nor steroids or 17-hydroxyprogesterone derivatives such as 6-medroxyprogesterone and naturally occurrit~g progesterone. Within limits, the effects of synthetic steroids are time-dose related, but even more ilnportant is synchronization of the steroid stimulation. Two types of regimen lmve been developed for contraception: (1) the combined regimen, ' in which a synthetic progestagen was combined with a synthetic estrogen into a single tablet taken for 20 or 21 days starting five days after the onset of bleeding, and (2) the sequential regimen in which an estrogen was taken for 15 or 16 days followed by six o1" five days in which the tablet con-
tained both a progestagen and an estrogen at tile same dosage. According to a third regimen, used for patients with pelvic endometriosis, tile combination tablet was taken continuously, without withdrawal for bleeding, and was often administered in stepwise monthly increments. One should remember that if ovulation is suppressed, the bleeding that follows withdrawal of the drug is not true menstruation. It is opportune to mention at this point that sequential medications have been voluntarily withdrawn from the market because they were less effective than combination therapy and were possibly associated with increased risks of thromboentbolism and endometriai adenocarcinoma (q.v.). 1 It is not widely appreciated that the effects of contraceptive steroids extend beyond their usual target organ. Irey, Manion, and Ta)'lor 2 and later Irey and Norris s described vascular lesions, predominantly intimal proliferation of a myxoid, fibrous, or celhtlar character, sometimes complicated by thrombosis, occurring in women taking contraceptives orally, in pregnant and postpartum women, and in men with severe liver disease. The absence of evidence of o t h e r disorders associated with intimal proliferation suggested its relation to endogenous and exogenous steroids. Tile final vascular compromise may be due to either severe narrowing by the intimal proliferation or a combination of that lesion with a thrombopathic state. Blaustein et al.4'5 had reported earlier regarding smooth muscle and endothelial proliferation in spiral arterioles deep in the endometrium of women taking contraceptives orally, and the possibility exists tlmt such changes are of a similar o r d e r of response. But the literature on this point remains sparse and no effort seems to have been made to investigate the nature of the vascular lesion by controlled studies in primates. Endometrium The endometrial changes associated with oral contraception vary with the time during tile treatment cycle at which a specimen is taken for histopathologic
EFFECTS OF CONTRACEI'TIVES ON T H E UTERUS--OnER stttdy as well as with the a m o t m t o f progestagen in the tablet. I'erhaps tire simplest approacit to the subject is historical. O n e o f the first "pills" to become available was Enovid, 10 nag., containing 9.85 rag. o f n o r e t h y n o d r e l and 0.15 mg. o f ethinyl estradiol, a strongly progestational formulation. A 21 year old woman who had undergone bilateral o6phorectomy four years previously desired to resume cyclical menstruation. A pretreatment biopsy disclosed an inert endometrium (Fig. 1). The endometrium was primed for three weeks with oral doses of stilbestrol, 1.25 rag. daily, which was tlten discontinued, with resultant withdrawal bleeding. On the fifth day after the bleeding began she received Enovid, 10 nag., for 20 days. On tire twenty-fifth day anotlter endometrial biopsy revealed small tubular glands, but the epithelium was somewltat lower than in the pretreatment specimen, indicating tlmt it migltt ltave gone through a secretory cycle (Fig. 2). The stroma showed a diffuse decidualike transformation. Spiral arterioles were not in evidence, but the endometrial venules were moderately dilated.
In ovttlating w o m e n studied subsequently it soon b e c a m e evident that tiffs basic pattern o f response to the c o m b i n e d r e g i m e n was fairly c o n s t a n t : At the end o f 20 days o f treatment, the a p p e a r a n c e o f the e n d o m e t r i u m gave rise to the term suppressed e n d o m e t r i t n n . T h e intensity o f the stromal decidual change varied widely f r o m patient to patient, but it was rarely absent at tire 10 mg. dose level. In some e n d o m e t r i a it was weak or sparse, but in tlte majority it was m o d e r a t e to strong. T h e d e g r e e o f dilatation o f venules also varied, being absent in about ltalf the specimens examined. By taking aspiration biopsy specimens at various stages in the t r e a t m e n t cycle, it was soon established that the endometrial glands did go t h r o u g h a secretory cycle3 Specimens obtained on cycle days 9 to 12 showed p r o m i n e n t subnuclear and s u p r a n u c l e a r secretory vacuoles, resembling those seen in the normal e n d o m e t r i u m o f ovulating w o m e n on cycle days 16 to 18. This p l t e n o m e n o n , labeled precocious secretion, was clearly the effect o f admin-
Figure 1 Figure 1. Inert endometriunl from 21 )-ear okl castrate.
Figure 2
Figure 2. Entlomeniunl after estrogen printing, withdrawal bleeding, and Enovid for 20 days. Note secretory exhaustion of glands, a decidua-like stromal change, dilated venules, and absence of spiral arterioles.
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HUMAN PATHOLOGY--VOLUME 8, NUMBER 5 September 1977
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istering a progestagen with an estrogen. Biopsy specimens taken later in the treatment cycle showed progressive regression of tlm precocious secretory reaction until hyperinvolution was seen circa day 20. Decidna-like stromal reactions were seen as earl)' as day 17, but spiral arterioles never sprouted toward tim surface epithelium. Subsequent formulations o f tlm combined "pill" reduced tim a m o u n t of progestagen needed to inhibit tlm pituitary gonadotropins and ovulation to the 5 rag. level, at wlfich point decidua-like stromal reactions became weak and infrequent. Still later formulations reduced tim a m o u n t of progestagen to 2.5 or even 2.0 rag., which was sufficient to inhibit ovulation. Tile clinical advantage of tiffs manipulation of dosage was to reduce "breakthrougll bleeding," an undesirable side effect (q.v.). At tiffs dose level there e m e r g e d tim picture of small endometrial glands lined by low epithelium without mitoses or secretion a n d e m b e d d e d in a loosely reticular, naked nucleus stroma; a decidua-like stromal reaction was extremely u n c o m m o n and no development of spiral arterioles or dilatation of venules occurred (Fig. 3). Tim use of sequential regimens supplied a somewhat opposite picture in the endometrium. During tim first 15 or 16 days of tim treatment cycle, tim patient received small doses of estrogen, either ethinyl estradiol or its 3-methyl ether, mestranol. Bioptic material taken d u r i n g tiffs plmse of the cycle showed only an estrogenic effect, i.e., tubular glands with increased mitotic activity but no secretion. Tim stroma was compact and of the naked nucleus type. Witlfin 48 hours after tim progestagen containing pill was added to the regimen, subnuclear and supranuclear secretory vacuoles appeared. Tiffs phen o m e n o n was labeled retarded secretion because it resembled tim normal pattern in ovulating subjects on days 16 to 18 but appeared in treated subjec{s on days 22 to 25. This secretory plmse was short lived, and regressive changes soon appeared. A weak decidua-like stromal transformation appeared circa days 24 to 25, but tim spiral arterioles remained suppressed. 8 Both tim combined and the sequential
--..
.,
Figure 3. Endometrium after Norgestrel, 0.5 nag., plus ethylestradiol, 0.05 mg., for 20 days. Note small tubular glands with no mitoses or secretion, loose reticular stronm with no predecidua, and no dilatation of venules or spiral arteriolar developme,m liner, Higher power view.
regimens are discontinuous, with tile medication stopped to permit cyclical withdrawal bleeding on schedule. Tile regimen for treating endometriosis differs in that it is continuous, with increments of the daily dosage of progestagenestrogen up to 30 mg. Withdrawal bleeding wonld be undesirable in patients with endometriosis because bleeding would also occur into tile pelvic tissues, producing the characteristic pain that the treatment was designed to abolish. Samples of endometrium taken at this high dosage level exlfibit a diffuse, intense decidual reaction that resembles that of decidua in tim first and second trimesters of pregnancy. Tim decidual cells are arranged in a pavement pattern, and tim glands are reduced to slitlike lumina, easily mistaken for small blood vessels (Fig. 4). Other regimens Imve been tried for
EFFECTS OF CONTRACEPTIVES ON T H E UTERUS-OBc~ for as long as one )'ear after the medication was stopped. T h e e n d o m e t r i u m after two o r t h r e e injections o f Depo-l'rovera was t h i n n e d and almost atrophic and was c o m p o s e d o f small h y p e r i n v o h l t e d glands in a compact, naked nucleus, stronta witltout vascular d e v e l o p m e n t (Fig. 6). T h e s e anatomic observations are based largely on material studied personall)', but tlte)" are in close a g r e e m e n t with those o f o t h e r reports. 'J-tt l'atterns Of endometrial response to oral adntinistration o f contraceptives tend to remain constant f r o m cycle to cycle over a period o f years) 2'~3 We have c o n f i r m e d this in o u r own studies o f biopsy specimens f r o m about 50 patients who were subjected to r e p e a t e d biopsy at intervals ranging f r o m one to 12 years while taking medication.Z4
Figure 4. Endometrium after six months of coqtixmous treatment with Enovid, 10 rag. daily, for endometriosis. Note intense decidual reaction and slitlike glands lined by flattened epithelium.
contraception but have p r o v e n unsatisfactory either because o f "breakthrougi~ bleeding," "postpill a n l e n o r r h e a , " or both. For example, a low dosage schedule o f Norgestrel, a potent progestational agent, given at a level o f 0.5 mg. daily and continuously, inlfibited ovulation, but breaktin'ough bleeding was a significant contplication. Endometrial biopsy after a few weeks o f medication showed small tubular glands lined by low epitllelium and an intense decidual reaction in tlte stroma witltout the d e v e l o p m e n t o f spiral arterioles (Fig. 5); dilatation o f venules was not a p r o n t i n e n t feature. Depo-Provera, administered intramuscularly at a level o f I00 rag. every three weeks or 200 mg. every six weeks, also inltibited ovulation, but a r e t u r n to cyclical menses was u n p r e dictable, and a m e n o r r h e a could persist
Figure 5. Endometrimn after low close Notgestrel nsed continuously. Note intense decidual reaction and glands lined by flat epitheliunl. Spiral arterioles are inhibited.
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Figure 7. E n d o m e t r i u m at the time o f " b r e a k t h r o u g h bleeding." Note laminated t h r o m b u s attached b)" a small base to the endothelium o f a dilated VCI|IIIC.
Figure 6. E n d o m e t r i u m after four injections o f Depo-Provera, 200 rag., at three m o n t h intervals. Glands are r e d u c e d to slits, and the entire mucosa is thinned. A weak predccidual reaction is present in the stroma, but spiral arterioles are not developed.
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One problem of interest is tile anatomic basis for "breaktln'ougll bleeding," i.e., unexpected bleeding during a treatment cycle. Most specimens taken shortly after the onset of bleeding reveal only hemorrhagic material, fragments of autolyzed endometrium, and debris. Occasionally a recent laminated thrombus is seen in a dilated venule within the superficial endometrium (Fig. 7). Tile thrombus seems to be atta~2hed by a snmll base mttch like those described by Irey et al.2"3 in larger vessels. The dilated venule also bears some resemblance to those so commonly found in hyperplastic endometria, and it is tempting to ascribe 9dilatation of the venules in women using contraceptives orally to the estrogen component of the pill. Some reinforcement of
this idea is supplied by collateral evidence in a study of quinestrol, a synthetic estrogen with no progestational properties. 15 In an occasional biopsy specimen obtained after a few months of medicaion, thrombosis and infarction have been seen in tile endometrium (Fig. 8), but there is good reason to believe tlmt in women receiving contraceptives orally the progestagen modifies tile response. Occasionally the pathologist may be confronted by an endometrial biopsy specimen from a patient with "postpill amenorrbea." The majority of women with tlfis complication probably did not have regular ovulatory cycles before orally effective contraceptives were prescribed, and such endocrinologic evidence as exists indicates a disturbance in the hypothalamus-pituitary axis. Usually tile pathologist is merely able to confirm by his examination of the endometrium that the patient is not ovulating, but occasionally he may detect weak or early evidence of secretory activity and issue an encouraging report. An early report by Dockerty et al. TM called attention to an unusual degree of
EFFECTS OF C O N T R A C E I ' T I V E S ON T H E U T E R U S - O B E R
Figure 8. Endometrium after quinestrol. Note mild glandular hyperplasia and marked dilatation of venules with thrombosis and local infarction.
e n d o m e t r i a l s t r o m a l p r o l i f e r a t i o n , labeled "pseudomalignant," in three women receiving p r o l o n g e d u n i n t e r r u p t e d p r o gestagen-estrogen medication. In rare instances atypical cells c a n be f o u n d in the e n d o m e t r i a l s t r o m a o f patients r e c e i v i n g c o n t r a c e p t i v e steroids, b u t s u c h cells a r e clearly b i z a r r e w i t h o u t a neoplastic c o n n o t a t i o n (Fig. 9).*
Cervical Glandular Epithelium U n l i k e the relatively u n i f o r m a n d p r e d i c t a b l e r e s p o n s e o f tile e n d o m e t r i u m , the e n d o c e r v i x reacts to c o n t r a c e p t i v e
*Editor's note: A role of oral administCation of contraceptive medication, specifically of the sequential type, in the development of endometrial carcinoma in young women has been suggested by the recent reports of Silverberg and Makowskit7 and Kaufman et al.,TM but the question of overdiagnosis of atypical growth patterns associated with estrogenic stimulation must be raised in cases of this type. This subject is discussed further in the Current Topic, "Estrogens and Endometrial Carcinoma," elsewhere in this issue.
Figure 9. Endometrium after Ortho-Novum. Note stromal cells with large, bizarre, hyperchrontatic nuclei. Inset, at higher magnification, reveals smudgy nature of nuclear material. Mitotic figures were absent.
steroids in a facultative way, a n d in m o s t instances tile histopatllologic c h a n g e s a r e unimportant. The endocrine milieu' c r e a t e d by tile ingestion o f a synthetic progestagen-estrogen is o f t e n t e r m e d " p s e u d o p r e g n a n c y , " a n d as in t r u e p r e g n a n c y o n e can o f t e n d e m o n s t r a t e an i n c r e a s e d h e i g h t o f the e n d o c e r v i c a l ceils and some degree of hypersecretion. T i l e i m p o r t a n t e n d o c e r v i c a l lesion was first d e s c r i b e d in 1967 by T a y l o r , I r e y , a n d N o r r i s , 19 w h o identified a distinctive atypical g l a n d u l a r p r o l i f e r a t i o n in 13 w o m e n r e c e i v i n g c o n t r a c e p t i v e s orally. T h e lesion was p o l y p o i d in m o s t o f tile cases. A m a j o r i t y o f tile patients w e r e asymptomatic, but some complained of postcoital o r i n t e r m e n s t r u a l spotting. T h e a u t h o r s e m p h a s i z e d the i m p o r t a n c e o f
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recognizing the benign nature o f the lesion. C a n d y and Abell z~ r e p o r t e d ano t h e r 12 examples; most o f their patients had polypoid or friable papillary lesions at o r p r o t r u d i n g f r o m the cervical os. Using the term microglandular hyperplasia, Kyriakos et al. 2~ r e p o r t e d 30 cases; three o f their patients were p r e g n a n t at the time o f biopsy, but one was neither p r e g n a n t n o r taking steroids orally. Govan et al. 2z r e c o r d e d 15 additional examples, 10 in contraceptors and five in p r e g n a n t women. T h e s e observers astutely pointed out that the lesion was cytoplasmic r a t h e r than nuclear and that it seemed to occur in pre-existing polypoid endocervical lesions m which reserve cell hyperplasia was already present. Nichols and Fidler e3 reviewed 128 consecutive cone biopsy specimens o f the cervix and f o t m d microglandular hyperplasia in 31 o f t h e m (24 per cent). Twentytwo o f the women (71 p e r cent) were using contraceptive steroids, but t h r e e w e r e p r e g n a n t and five who were not using contraceptives orally at the time o f biopsy
had nsed t h e m within the previous )'ear. Many o f the lesions in tiffs series were snmll and were detected only because n u m e r o u s sections were made o f the specimen. In some instances multiple small discrete loci were scattered at r a n d o m in the endocervical mucosa. T h e authors advanced the hypothesis that a progestagen was necessary for the lesion to develop but not necessary for its support. T h e morphologic features o f microglandular hyperplasia, w h e t h e r polypoid or not, consist o f a h o n e y c o m b or cribrif o r m mass o f tightly packed acini, varying somewhat in size and shape but mostly irregular. T h e glands are lined by a low cuboidal to flattened single layer o f nlucns secreting epitheliun~ and do not seem to be invested with basement m e m b r a n e like normal endocervical glands. T h e r e is little variation in nuclear size, shape, or staining properties, and mitotic figures are sparse (Figs. 10, 11). In polypoid excrescences the impression is one o f a syncytial o u t g r o w t h f r o m a mildly inflamed base. Leukocyte infiltration is
Figure I0. l.ow power view of polypoid excrescence of endocervix after 20 cycles of Enovid, 5 rag. 9 Note the lacy pattern of microglandular hypcrplasia.
Figure 11. Higher magqification of Figure 10. Note closely packed glands lined by uniform cuboidal cells with vesicular nuclei. The glands contain nltlctls. but mitosesare not seen. A normal endocervical gland is included for comparison.
EFFECTS OF CONTRACEPTIVES ON THE UTERUS-OnER COllllnon; if ulceration is present, neutrophils predominate, but in intact lesions plasma cells and eosinophils are often abundant. Czernobilsky et ai.2~ have reported a single case o f papillary adenocarcinoma of the endocervix in a 25 )'ear old woman who had been receiving combined-regimen contraceptives orally (ethynodiol diacetate and mestranol) for f o u r )'ears. Presumably this was a coincidental association, but pathologists should be on guard for f u t u r e anecdotal material of this nature.
CervicalSquamous Epithelium T h e squamous epithelium is even less prominent a target for synthetic steroids than the glandular epithelium. A n u m b e r of pertinent histopathologic or cytopathologic studies have been carried out, and discrepancies exist. Some of the confilsion can be traced to differences of interpretation, but some is also due to the types o f populations investigated. A combined cytologic and histologic study o f over I00 randontly selected patients u n d e r the age of 50 )'ears receiving contraceptives orally at the family planning clinic o f an arm)' hospital failed to disclose significant lesions, t h o u g h minor aherations a b o u n d e d in the biopsy specimens. 25 A colposcopically guided study of cervical biopsy specimens taken both before and after medication in 58 muhiparous Mexican women with a mean age of 30+ years revealed no precancerous lesions. ~6 Perhaps the most reassuring report is the retrospective study of 196 women with invasive cervical cancer who exhibited no difference in their oral use of contraceptives fi'om that of a carefully selected set of controls matched for age, ethnic background, age at first coitus, age at first pregnancy, n u m b e r of pregnancies, and socioecononfic status. 27 Another retrospective study based on 324 wonten with cytologic smears suggestive o f neoplasia, matched with 302 controls, led to the conclusion that those women using contraceptives orally for a mean tSeriod of 20 months were no more likely to have squamous metaplasia or carcinoma in situ within two and one-half
to three years after tile initiation of therapy than women who did not use contraceptives orally. 2s Tile limitation of this study lies in the short interval of observation; one would expect a longer latent period for carcinogenesis related to hormones. An extensive study by Melamed et al.29 compared the exfoliative cytology in 27,500 women using steroids orally for contraception with that in 6800 women using the diaphragm. T h e statistical complexities are formidable, but the authors concluded that there was a small but statistically significant increase in the prevalence rate of carcinoma in situ a m o n g the women choosing and using orally effective steroids. Tlle authors caution that this increase call be attributed either to a decreased prevalence rate a m o n g women using the d i a p h r a g m or to an increased rate a m o n g those using orally effective steroids; the reason for tlle difference was not apparent fi'om their data. In a later study fi'om tile same clinic the authors reported an incidence rate of biopsy proven carcinonta ill situ of 2.3 in steroid users compared with 1,4 in diap h r a g m users, and 1,4 ill steroid users compared with 0.6 in women using an intrauterine device, a9 Tile numerical values indicate that the use of a barrier type o f contraceptive, i.e., the diaphragm, may not be quite so effective a protection against transformation of the squamous epithelium as formerly imagined, but the influence of motivational factors in selecting tile method for contraception cannot be excluded. Lacking in this and similar studies is an account o f the sexual activity of the women at risk, especially those in tile y o u n g e r age groups with early and frequent coital exposures to an assortment o f male partners. T h e cervix was not designed by nature as a trampoline, and sexual activity rather than oral steroid medication or ahernative methods for contraception may be decisive. T h a t the prevalence rates given by Melamed et al. are higher than in .other clinics has been noted by m a n y and is often attributed to origfin fi'om a l'lanned P a r e n t h o o d population in New York with all the innuendoes about the mores of that " f u n city." But the study by Kline
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HUMAN PATHOLOGY--VOLUME 8, NUMBER 5 September1977 et al.3t from Boston indicates a 2.0 per cent rate of abnormality in both squamous and endocervical cells in a population of 2300 women receiving contraceptive steroids, contrasted with a 1.0 per cent rate in over 17,000 women not receiving steroids. Lacking in both studies is an}' comment regarding the fi'equency of the "atypia of pregnancy," a reversible cytologic finding that can readily be accounted for by tile state of pseudopregnancy induced by the progestagen-estrogen preparation. In a sense Doughert} a2 supports the numerical values of Kline et al., having found twice the expected rate of cytologic atypia ill a continuous study of repeated smears from ahnost 2000 women receiving sequential steroid contraceptive medication in a Louisiana clinic. A prospective study by Stern et al? 3 fi-om Los Angeles found "dysplasia" in 9.0 per cent of tile cytologic smears in pill users, 5.3 per cent in intrauterine device users, and 3.7 per cent in diaphragm users. These numerical vahles support tile idea that a barrier contraceptive does protect tile cervical squamous epithelium fi'om atypical cellular changes, and the authors relate their findings to factors in the decision making ln'OCeSS at the time of contraceptive counseling. It is ditlicuh for a lfistopathologist to evaluate a report of tiffs nature, whicll is not supported by biopsy material and accepts "dysplasia" as an index of carcinogenic potential without a description or qualification of the term. The study by Worth and Boyesa~ from British Columbia was based on "preclinical carcinoma," another term tlmt is difficult to define with precision. Analyzing 310 cases so diagnosed, matched with 682 controls, they fotmd no difference in contraceptive usage, but they did find an increased frequency in the women with preclinical carcinoma in abnormal marital situations, including mtditple marriages, divorces, and common-law relationships. These women also had a higller preguancy rate and parity than the controls, and their age at first pregnancy was younger and antedated the age at marriage-suggesting, as the authors politely phrased it, "a different pattern of belmviour in the two groups." The most recent stud}' of importance
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to deal with this question is by Dabacens et al. z5 fi'om Santiago, Chile, who compared 2400 women using an intrauterine device for 3200 woman-years with almost 2700 women using long acting injectable progestagens (chlormadinone acetate and medroxyprogesterone acetate) for over 7000 woman-years. The subjects were studied by repeated cytologic examinations, colpomicroscopy, and punch biopsy or cone biopsy as indicated. The authors concluded that tile incidence rate of new lesions appearing during the use of these contraceptive methods was the same for both groups. Despite the unresolved differences of opinion, it is reasonable to quote the conclusions from Dougherty's article? 5 1. The pills do not protect against cancer. 2. The pills do not cause cancer in the generally accepted meaning of this stateInent.
Myometrium Attention was directed to the effects of steroid induced pseudopregnancy oil the myometrium quite early when Andrews et al. 36 reported progressive enlargement of uterine leiomyomas in seven women being treated with continuous progestagen-estrogen medication for peh, ic endometriosis. Three of these women required hysterectomy, and microscopic examination of their leiomyomas showed "typical pregnancy hypertrophy." Tile tumors in the remaining four patients returned to their original size after the medication was stopped. A case of acute hemorrhagic degeneration of a leiomyoma was reported by Briscoe, a7 but the patient had received Norlutate, 5 rag., for only three days before "bursting" suprapubic pain was reported. One suspects tlmt circulation to the pre-existing leiomyoma was already compromised before the medication was started. On microscopic examination tile tumor was celhdar and actively growing; extensive edema separated individual smooth muscle cells and bundles, and there was pronounced dilatation of engorged veins with irregular zones of hemorrlmge as well as foci of acute necrosis. Because of reports like these, the
EFFECTS OF CONTRACEPTIVES ON THE UTERUS--OgER presence of palpable leiomyomas was generally considered a contraindication to prescribing contraceptive steroids. Prakash and Scullyas reported a case in which Norethindrone, administered in dosages ranging from 30 to 60 mg. daily for 14 months, produced progressive enlargement of a uterine leiomyoma. In addition to hypercellularity, edema, and foci of necrosis,.the tumor contained cells with large bizarre layperchromatic nuclei resembling those seen in leiomyosarcomas so closely that tim authors labeled the changes "sarcoma-like" and cautioned against overinterpretation of such responses. In tiffs striking case the medication used contained no added syn-
thetic estrogen, though contamination with traces of estrogen in its manufacture could not be exch, ded. The implication was that the accelerated growth response and atypia could be purely a progestational effect. Later Fechner a9 reviewed the problem and added five cases of Iris own. In addition to large irregular hyperchromatic nuclei he illustrated cases in wlfich the nuclei were multilobated. It is sometimes difficult to judge whether in some specimens there may not be multiple nuclei forming a plasmodium-like syncytlunl (Fig. 12). Mitotic figures, which are the best index of malignancy in cellular smooth muscle tumors, are usually present in slightly increased numbers, but a true leiomyosarcoma in a patient receiving contraceptive steroids has yet to be reported. In examining routine sections for mitotic activity, it is extremely important not to include pyknotic nuclei whose crenated borders may suggest nuclei in anaphase. EFFECTS OF I N T R A U T E R I N E DEVICES
Figure 12. Uterineleiomyomagrowingrapidly in womantakingcontraceptivesorally.Noteincreased celh,larity with many large h)'perchronmtic nuclei.. Inset, Higher magnificationshowing muhinudeated smooth musclesyncytia.
Grtifenberg's silver ring was tile first usable intrauterine contraceptive device of the modern era. Developed in tile 1920's, it had only limited application and fell into desuetude for a number of reasons but was recalled to memory when devices made from molded polyethylene plastic or from metal began to compete with synthetic steroids. Tile convenience of a contraceptive method that requires only a single insertion is self-evident. There has been considerable debate about tile mechanism whereby intrauterine devices prevent pregnancy. Animal experiments have indicated considerable species variation in the contraceptive mechanism of polyethylene devices. The consensus is that a mild nonbacterial intlammatory response is in some way involved. Electron microscopic studies have shown platelet-like thrombi in endometrial capillaries, damage to the surface epithelium near contact points, and asynchronous premature maturation of the endometrium. ~~ But tim frequent observa-
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HUMAN PATHOI.OGV--VOLUME 8, NUMBER 5 September 1977 tion o f an e x u d a t i o n o f p o l y m o r p l m n u clear lenkocytes c a n n o t be discounted. 4 Col)per bearing devices also elicit a polym o r p h o n u c l e a r e x u d a t i o n , but in addition the cupric ion inhibits several e n z y m e systems?" Inhibition o f alpha-amylase interferes with the n o r m a l cyclical increase in glycogen, and inhibition o f carbonic a n h y d r a s e can lead to a local increase in bicarbonate ion; perhaps failure o f both these enzyme systems creates an unfavorable tissue milieu for nidation. Inevitably insertion o f a device t h r o u g h the endocervical canal will introduce bacteria into the cavum uteri. Tim early study by Misheli et al. 4a d e m o n strated that the u t e r u s sterilizes itself from such contaminants after a month. Presumably most o f tim bacteria are not patlmgenic. But in a certain p r o p o r t i o n o f device users, e n d o m e t r i a l inflammation develops, p r o d u c i n g bleeding, vaginal discharge, and peh'ic pain. O b e r et al. 4~'4~ r e p o r t e d a 25 per cent fi'equeqcy o f significant endometritis in syml)tomatic polyethylene device users a n d d e m o n s t r a t e d that this rose to a 40 p e r cent level as the time o f e x p o s u r e was p r o l o n g e d to m o r e than three years. Squamous metaplasia o f the e n d o n m t r i u m was f o u n d in several cases and occasionally foreign body giant cells were e n c o u n t e r e d (Fig. 13). Intlammatory reactions of the e n d o m e t r i u m are only slightly less fi-equent in association widl c o p p e r b e a r i n g devices; a c o m m o n pattern is the presence o f I m l y m o r p h o n u clear leukocytes in glandular hnnina with a thin layer o f e x u d a t e on tim surface but without leukocytic infiltration o f tim stroma (Fig. 14). T w o specific incidents r e g a r d i n g endometritis associated with intrauterine devices merit citation. T h e Majzlin spring p r o d u c e d severe intense endometritis in m a n y patients within a few months o f insertion, a6 T i m spring was m a n u f a c t u r e d f r o m stainless steel that contained about 18 per cent chronfiuna and 9 per cent nickel in the alloy; both these metallic runs are highly irritating to mucosal surfaces. T h e Dalkon shield, m a n u f a c t u r e d from ethylvinyl acetate i m p r e g n a t e d with c o p p e r sulfate and metallic copper, was associated with 209 septic midtrimester abortions and 11 maternal deaths. T a t u m
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Figure 13. Endometrium following t,se of intrat*terme contraceptive device. Note squamous metaplaskl of stirface with basal cell hyl)eqflasia .rod chronic inIkunmation in the sub.jacen~ mucosa. (PA5 stain.) et al. 47 f o u n d that although the tail o f most o t h e r devices was a single or double monofilament thread, the tail for the Dalkon shield was c o m p o s e d o f either 400 (standard size) or 200 (small size) filaments in a plastic sheath. T h e wicklike action o f tile tail p e r m i t t e d fluid and bacteria to ascend f r o m tile vagina into the uterine cavity. Electron micrographs have revealed bacteria in tim interstices between tim filam e n t s . A c o m p a r a b l e tail was used o n the Majzlin spring. Both devices lmve been withdrawn by the nmnufacturer. Unless pelvic infection develops or p r e g n a n c y supervenes, the endometritis associated with intrauterine devices is usually self-limited. Even wllen biopsy has shown chronic productive endometritis at the time o f removal, rebiopsy after two or t h r e e cycles without the device shows that the inflammation has disappeared. At such time it may be a p p r o p r i a t e to insert a fl'esh device if c o n t i n u e d contraception by tlmt m e t h o d is desired. It is difficult to calculate the role o f intrauterine devices in relation to tile incidence o f saipingitis, salpingo-o6phoritis,
EFFECTS OF CONTRACEPTIVES ON THE UTERUS--OBER
Figure 14. Endometrium following use of intrauterine contraceptive device (copper T). Note glandular lumina filled with polymorphonuclear leukocytes exuding to form a catarrhal membrane on the surface. T h e r e is no leukocytic reaction in the endonletrial stroma.
an antigonococcal effect, no one has suggested that it is prophylactic against infection by that organism. Needless to say, pathogenic micro-organisms recovered from clinical cases of pelvic infection show diversity and heterogeneity of species. Another potential complication of intrauterine devices is ectopic pregnancy. Recent data indicate that in copper T users, 3,4 per cent of pregnancies are extrauterine, a value higher titan that usually given for the general population. ~ There is no doubt that accidental pregnancy in a device user (method failure) does carry a high risk of complication. Excluding the 55 to 60 per cent of women who elect abortion, about 15 have a spontaneous abortion and only 20 per cent lmve a live birth. Even more dangerous than pelvic infection or accidents of pregnancy are the occasional examples of intestinal obstruction tlmt occurs when an intrauterine device perforates the uterus and becomes entangled with omentum and loops of bowel. Given a large enough volume of material, pathologists can expect to see all the complications enumerated.
ACKNO~,VLEDGblENTS
tubo-ovarian abscess, and other forms of pelvic inflammatory disease. Far too many uncontrolled variables combine to make analysis of data treacherous. In the best controlled study by Mead et al.,4s-41 per cent of all women admitted with acute pelvic infection wore intrauterine devices, and presumably this is a higher figure than tim percentage of device users in the general p o p u l a t i o n - b u t the latter number cannot be determined. Further, over half the patients with pelvic sepsis were using either the Dalkon shield or the Majzlin spring; presumably other devices are safer. Nine cases of septic abortion occurred, all in Dalkon shield wearers. Only two cases yielded isolates of N. gonorrheae. But it is difficult to be certain whether the risk of pelvic infection should be assigned to tim device or to promiscuity. Altlmugll tim cupric iota has
From 1960 to 1973 I had tim pleasure and privilege of serving as consulting pathologist at tile Margaret Sanger Research Bureau and from 1961 to 1972 at the New York Fertility Institute. During this period many of the drugs and devices now used for contraception were being tried and tested. To collaborate with my clinical colleagues in this work was a challenge and a rewarding experience. No bistopathologist can reach beyond tile material given him by his clinical associates nor is he likely to provide answers to questions they do not put. It was also my pleasure to share this unique pathological material, which I had in such abundance, with my fellow pathologists in a series of articles dating from that period, i must acknowledge the generous and friendly cooperation of Doctors Aquiles J. Sobrero and Jeaane C. Epstein of tim Margaret Sanger Research Bureau and of Doctors
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8, N U M B E R 5
M a r t i n J. C l y m a n a n d M a x w e l l R o l a n d o f t h e N e w Y o r k F e r t i l i t y I n s t i t t t t e . B u t this e s s a y is d e d i c a t e d to t h e m e m o r y o f t h e late D o c t o r s L e n a L e v i n e a n d M i l d r e d E. W a r d of the Bureau, two compassionate gTnecoiogists whose idealism informed their c l i n i c a l skills a n d w h o i n s p i r e d u s all.
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