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Cribriform polypoid adenomatous (atypical) hyperplasia of the endocervical glands of the uterus under hormonal contraception
EUROP. I. OBSTET. GYNEC. REPROD. BIOL., 1977,7/5,331-336 0 Elsevier/North-Holland Biomedical Press
Cribriform polypoid adenomatous (atypical) hyperplasia of the endocervical glands of the uterus under hormonal contraception L. Moltz and K. Becker Division of Gynecological Endocrinology, Sterility and Family Planning, Department of Obstetrics and Gynecology, Steglitz, Freie Universittit Berlin, 1000 Berlin 45, Hindenburgdamm 30, Federal Republic of Germany
Klinikum
MOLTZ, L. and BECKER, K. (1977): Cribriform polypoid adenomatous (atypical) hyperplasia of the endocervical glands of the uterus under hormonal contraception. Europ. .I. Obstet. Gynec. reprod. Biol., 7/S, 331-336. The occurrence of cribriform adenomatous hyperplasia of the endocervical glands of the uterus was examined in 92 women, in whom punch biopsies of the ecto-endocervical line were taken during the second half of their cycle. Of these, 79 women had taken combined estrogen-progestogen preparations, 9 women had taken progestogens alone, while 14 patients formed a control group. There was a significant difference only between the control group without hormones and the groups treated with hormones. The groups of patients under the various regimes of hormonal treatment displayed a varying percentage of cribriform adenomatous hyperplasia. There was a clear tendency for such lesions to be observed more frequently under the combined type of contraception than under the sequential type. These differences were not, however, significant. A correlation with specific exoge-
nous groups of steroids could not be established. hormonal contraception; atypical hyperplasia
Konikov, 1968) and a number of patients seem to have been treated wrongly - as if they were suffering from cervical carcinoma (Candy and Abell, 1968). It is therefore all the more important for every histopathologist to know about this “histopathology of treatment” (Seidl, 197 1) which, as has been shown in an unpublished study by Moltz, Joschko and Neuser described below, is reversible. Unfortunately only little is known about the incidence of this type of hyperplasia. The histological examination of biopsies and cone sections taken from women with suspect cytological smears or suspect colposcopic findings has shown that the frequency of occurrence of this hyperplasia ranges between 25% and 45% (Gmiir, 1970; Nichols and Fidler, 1971). Joschko and Neuser (1975) were the only ones to examine unselected
Introduction
Since 1967 a number of studies have been conducted on atypical hyperplasia of the endocervical glands of the uterus. An association between these changes and the use of oral contraceptive agents was common to almost all the cases described. The endocervical hyperplasia was all the more striking since it was sometimes combined with epithelial disturbances. Differentiation from adenomatous carcinoma was very difficult in some cases (Bahrmann, 197 1; Taylor, Irey and Norris, 1967; Candy and Abell, 1968; Talbert and Sherry, 1966; Seidl, 1971; Czernobilsky, Kessler and Lancet, 1974; Gall, Bourgeois and Maguire, 1969; Graham, Graham and Hirabayashi, 1968; Haberich, 1970; Kyriakos, Hempson and 331
332
L. Moltz and K. Becker: Endocervical hyperplasia under hormonal contraception
biopsies, and they found the hyperplasia in 32% of their specimens, Since no clarity exists as regards the conditions which give rise to this lesion, we have tried to analyze its incidence in unselected biopsies in relation to the components of different hormonal contraceptives.
TABLE I
Composition
Anacyclin DepoClinovir Eugynon Lyndio12.5
Material and methods
Microgynon Neogynon
an unpublished study by Moltz, Joschko and Neuser from 1970-1972 it was demonstrated that, of 356 women practising contraception with a combined preparation (0.08 mg mestranol and 2.0 mg chlormadinone acetate), 111 displayed cribriform hyperplasia of the endocervical glands. In a control group consisting of 164 women who were not taking hormones, no changes of this nature were observed. Preselection on the basis of, for example, changed cytological or colposcopic findings did not take place. The groups differed neither in respect of their mean age nor in their parity. All 111 patients with a positive histological finding underwent a second histological examination at the earliest 6 mth and at the latest 42 mth later. During this period of time 24 of the women received no more hormones at all, and only 4 of them still displayed hyperplasia at the time of the second examination - one of them even after 42 mth. Of 36 patients who continued to use the same combined preparation, 24 displayed a positive finding at the time of the second histological examination. The other 51 patients were switched to a different combined preparation (0.08 mg mestranol and 1.0 mg norethisterone acetate), but 26 of them still displayed a positive histological finding. According to the x2 test with a 1% probability of error, the association between cribriform hyperplasia of the endocervical glands and the administration of hormones is significant. This hyperplasia is evidently reversible after discontinuation of the hormone therapy. For this paper unselected punch biopsies of the endo-ectocervical line were taken from 92 women in the second half of their menstrual cycle (using sample biopsy forceps, model Aesculap with biopsy insert, Wolff KG). The age of the women varied between 17 and 46 yr (mean age 25.06). Of these 92 women, 14 (mean age 25.0) had not taken any hormones at all for more than 1 yr. The remaining 78 had taken In
Noracyclin Nuriphasic Oraccnal Orgametril Ortho-Novum l/80 Ortho-Novum Ovanon Ovulen Planovin Primolut-Nor Tri-Ervonum
l/SO
of the hormone preparations used
1 .O mg lynestrenol; 0.05 mg ethinylestradiol 150 mg medroxyprogesterone acetate 0.5 mg d-norgestrel; 0.05 mg ethinylestradiol 2.5 mg lynestrenol; 0.05 mg ethinylestradiol 0.15 mg d-norgestrel; 0.03 mg ethinylestradiol 0.25 mg d-norgestrel; 0.05 mg ethinylestradiol 2.5 mg lynestrenol; 0.05 mg ethinylestradiol O/2.5 mg lynestrenol; 0.08/0.075 mg mestranol O.l/l.O mg megestrol acetate; O.l/O.l mg ethinylestradiol 5 mg lynestrenol 1 .O mg norethisterone; 0.08 mg mestrano1 1.0 mg norethisterone;0.05 mg mestranol O/2.5 mg lynestrenol; 0.08/0.075 mg mestranol 1.0 mg etynodiol diacetate; 0.1 mg mestranol 4.0 mg megestrol acetate; 0.05 mg ethinylestradiol 5.0 mg l’lol-ethinyl-19.nortestosterone acetate O.l/l.O mg megestrol acetate; O.l/O.l mg ethinylestradiol
hormones over a period of at least 6 mth immediately prior to the biopsy. Combined-type oral contraceptives were taken by 49 women with a mean age of 26.48 yr (10X Microgynon, 8X Neogynon, 1X Eugynon, 6X Lyndio12.5, 4X Planovin, 4X Noracyclin, 7X Anacyclin, 4X OrthoNovum l/50, 4X Ortho-Novum l/80, 1X Ovulen), sequential type by 20 women with a mean age of 27.07 yr (1X Oraconal, 17X Ovanon, 1X Tri-Ervonum, 1X Nuriphasic), while 9 (mean age 33.31 yr) were treated with progestogens alone for various reasons (5X Depo-Clinovir, 3X Orgametril, 1X Primolut-Nor) (Table I). The specimens were fixed in forrnalin and embedded in paraffin. Each sample was cut serially and the sections were stained with hematoxylin and eosin. The characteristics of the ‘cribriform adenomatous hyperplastic gland tissue’ of the cervix uteri
L. Moltz and K. Becker: Endocervical hyperplasia under hormonal contraception
333
Fig. 1. Normal endocervical glands.
Fig. 2. Cribriform adenomatous hyperplasia of endocervical vacuoles and the hyperplasia of the reserve cells.
glands. Note the reticular formation
of the cells, the intracellular
L. Moltz and K. Becker: Endocervical hyperplasia under hormonal contraception
334
were (Bahrmann, 1971; Seidl, 1971): -loss of original gland structure and cell polarization, the cells forming reticular structures and small alveoli, like a tine sieve; - intracellular vacuoles; - hyperplasia of reserve cells. A specimen was regarded as positive only if the changes were so obvious that there could be no doubt about the finding (Figs. l-2), regardless of their extension to a part of a gland, to a single gland or to several glands. The 1‘I-ketosteroids were determined according to the method of Zimmermann (1955) and the 17.hydroxysteroids according to the method of Few (1961).
to the x2 test the difference between the two groups is significant with a 5% probability of error. These changes were exhibited by 45% of the patients taking the combined type of contraceptive, by 30% of the patients taking the sequential type and by 44% of the patients taking progestogens alone (Table II). There was no significant difference between the treatments - combined or sequential type of contraception or progestogens alone. As regards the estrogen component - ethinylestradiol (EE) in 28 cases with a mean age of 28.4 yr and mestranol (EEME) in 41 cases with a mean age of 23.99 yr - the percentage of positive findings was 39% and 41%, respectively. The difference between these results is not significant. There were no statistically significant differences between the most frequently used progestogens, lynestrenol 35% and d-norgestrel32%. The results did not change even when estrogenic side effects were considered. An elevated adrenocorticoid activity which has been reported previously (Kaiser, 1969) could not be confirmed. The excretion of 17.0~0 and 17.hydroxy corticoids in the urine of 12 patients with cribriform adenomatous hyperplasia did not exceed the normal range.
Results The incidence of cribriform adenomatous hyperplasia in the 78 patients who had taken hormones was 4 l%, regardless of age. Of the 14 women who had not taken hormones for more than 1 yr, only 1 - a patient who had stopped taking i.m. medroxyprogesterone acetate as a contraceptive agent 18 mth before the biopsy - displayed a positive finding. According TABLE II
Frequency treatment
of cribriform
adenomatous
Type of hormone
hyperplasia
of the endocervical glands in relation to the type of hormone
No. of test subjects
Cervical gland hyperplasia of the small alveoli Amount
No hormone therapy Combined preparations Sequential preparations Gestagens only Ethinylestradiol (EE) Mestranol (EEME) Lynestrenol d-Norgestrel EE + d-Norgestrel EEME + Lynestrenol Gestagens with partial estrogenic effect Gestagens without partial estrogenic effect (a) Megestrol acetate (b) Medroxyprogesterone
l Seetext.
14 49 20 9 28 41 38 19 19 32 48 30 6 5
Percentage
Pos.
Neg.
Pos.
Neg.
1’ 22 6 4 11 17 17 6 6 14 21 11 4 1
13 27 14 5 17 24 21 13 13 18 27 19 2 4
7 45 30 44 39 41 35 32 32 44 44 37 67 20
55 70 56 61 59 65 68 68 56 56 63 33 80
93
L. Moltz and K. Becker: Endocervical hyperplosia under hormonal contraception Discussion
Knowledge about histological lesions of the endocervical glands of the uterus relating to hormonal treatment goes back several years. Estrogens (Seidl, Hellmann, Dallenbach-Hellweg, 1969; 1971; Rosenthal, Kistner and Gordon, 1954) as welI as progestogens (Kaiser, 1969; Dallenbach-Hellweg, 1969 ; Dallenbach-Hellweg, Harting, Momber and Thorn, 1971; Dito and Batsakis, 1961; Maqueo, Azuela, Calderon and Goldzieher, 1966) are thought to lead to hyperplastic changes. Lesions similar to cribriform adenomatous hyperplasia were found by Nichols and Fidler (197 1) in 5 patients and by Candy and Abel1 (1968) in 1 patient treated with a progestogen alone and by Hellman et al. (1954) in 12 patients treated with an estrogen alone. Because of the similarity of cribriform adenomatous hyperplasia to alterations of the endocervical glands during pregnancy (Bahrmann, 1971; Seidl, 1971; Nichols and Fidler, 1971; Govan, Black and Sharp, 1969; Hamperl, Kaufmann and Ober, 1954), progestogens were thought to be the cause of such lesions. On the other hand, most of the women under oral contraceptives with this lesion had been taking mestranol in addition to the progestational agent, so this particular estrogenic compound has also been thought to be responsible for this kind of hyperplasia, particularly in view of its proliferative effect (Seidl, 1971). The results obtained in our studies do not support either of these interpretations, nor were any differences observed in respect of the estrogenic, androgenic and/or antiandrogenic partial effects of the various progestational agents. This appears to be true for chlormadinone acetate as well (Joschko and Neuser, 1975). The statistical evaluation of our results is, however, limited by the relatively small number of cases. It must also be borne in mind that, with a biopsy, only a very small specimen of the whole endo-ectocervical zone is examined. In our population of unselected patients there was no indication for larger intervention, e.g. conization. All that can be said is that these changes appeared almost exclusively under treatment with exogenous sex hormones. As already mentioned on p. 332, there are apparently rare cases in which the hyperplasia persists over protracted periods of time - in 1 case for as
335
long as 42 mth. This could quite easily be the explanation for the 1 positive finding in the group of untreated patients. The changes of the endocervical glands during pregnancy are similar but can usually be differentiated from cribriform hyperplasia of the endocervical glands (Seidl, 1971), particularly in late pregnancy. As far as is known, it is not possible to produce an explanation as to why positive findings could only be found in a certain percentage of women under such treatment. Because the histological changes disappear almost completely within 1% yr after discontinuation of the hormonal treatment (see p. 334), and since not a single case of adenomatous carcinoma is so far known to have developed from the cribriform adenomatous hyperplasia, it can be assumed that this is a harmless lesion that is not to be compared with precancerous stages or adenocarcinomata. Confusion with adenocarcinoma is, in any case, only possible in the few cases of greatly pronounced epithelial unrest. No changes of this kind were observed in the present 76 specimens.
References Bahrmann, E. (1971): Polypoide Zervixdriisenhyperplasie am ausseren Muttermund mit Epithehmruhe nach hormonaler Kontrazeption. Zbl. Gytik., 93, 1973. Candy, M. and Abe& R. (1968): Progesteron-induced adenomatous hyperplasia of the uterine cervix. J. Amer. med. Ass., 203, 323. Czernobilsky, B., Kessler, 1. and Lancet, M. (1974): Cervical adenocarcinoma in a woman on long-term contraceptives. Obstet. and Gynec., 4, 517. DaBenbach-Hellweg, G. (1969): Endometrium, Monographie, S. 36. Springer-Verlag, Berlin-Gottingen-Heidelberg. Dallenbach-Hellweg, G., Harting, W., Momber, F. and Thorn, V. (1971): Zytologische und histologische Untersuchungen der Portio und Cervix uteri unter der Einnahme von Ovulationshemmern. Fortschr. Med., 89, 883. Dito, W.R. and Batsakis, J.G. (1961): Norethynodrel-treated endometriosis: a morphologic and histochemical study. Obstet. and Gynec., 18, 1. Few, J.D. (1961): A method for the analysis of urinary 17hydroxycorticosteroids. J. Endocr., 22, 31. Gall, S.A., Bourgeois, C.H. and Maguire, R. (1969): The morphologic effects of oral contraceptive agents on the cervix. J. Amer. med. Ass., 207, 2243. Gmtir, H. (1970): Die Wirkung der Ovulationshemmer auf Portio- und Zervixschleimhaut. Inaugural Dissertation, Medical Faculty, University of Zurich.
336
L. Molts and K. Becker: Endocervical hyperplasia under hormonal contraception
Govan, A.D.T., Black, W.P. and Sharp, J.L. (1969): Aberrant glandular polypi of the uterine cervix associated with contraceptive pills: pathology and pathogenesis. J. clin. Path.s22, 84. Graham, J., Graham, R. and Hirabayashi, K. (1968): Reversible ‘cancer’ and the contraceptive pill. O&et. and Gynec., 31, 190. Haberich, M. (1970): Histologischer Beitrag zum sog. Cervixfaktor der Ovulationshemmer, Ref. in: Zbl. allg. Path., 113, 258. Hamperl, H., Kaufmann, C. and Ober, K.G. (1954): Histologische Untersuchungen an der Cervix schwangerer Frauen. Arch. Gyrui:k.,184, 181. Hellmann, L.M., Rosenthal, A.H., Kistner, R.W. and Gordon, R. (1954): Some factors influencing the proliferation of the reserve cells in the human cervix. J. Obstet. Gynec., 67, 899. Joschko, K. and Neuser, D. (1975): ‘Siebartige polypoide Zervixdriisenhyperplasie’ nach oralen Kontrazeptive. Zbl. Gyrufk., 97, 25. Kaiser, R. (1969): Zur Atiologie und Prophylaxe des Endometriumkarzinoms. Geburtsh. u. Frauenheilk., 5, 431.
Kyriakos, M., Hempson, R.L. and Konikov, N.F. (1968): A clinical and pathologic study of endocervical lesions associated with oral contraceptives. Cancer, 22, 99. Maqueo, M., Azuela, J. Ch., Calderon, J.J. and Goldzieher, J.W. (1966): Morphology of the cervix in women treated with synthetic progestins. Amer. J. Obstet. Gynec., 96, 994. Nichols, T.M. and Fidler, H.K. (1971): Microglandular hyperplasia in cervical cona biopsies taken for suspicious and positive cytology. Amer. J. clin. Path. 56, 424. Seidl, St. (1971): Atypische endozervikale Hyperplasien bei hormoneBer Kontrazeption. Geburths. u. Frauenheilk., 31, 1006. Talbert, J.R. and Sherry, LB. (1966): Adenocarcinoma-like lesion of cervix - a ‘pill induced problem’? Amer. J. Obstet. Gynec., 105, 117. Taylor, H.B., Irey, N.S. and Norris, H.J. (1967): Atvuical endocervical hyperplasia in women taking oral contraceptives. J. Amer. med. Ass., 202. 637. Zimmermann, W. (1955): Chemtsche Bestimmungsmethoden von Steroidhormonen in Klirperfliissigkeiten. SpringerVerlag, Berlin-Gottingen-Heidelberg.
Cribriform polypoid adenomatous (atypical) hyperplasia of the endocervical glands of the uterus under hormonal contraception L. Moltz and K. Becker Division of Gynecological Endocrinology, Sterility and Family Planning, Department of Obstetrics and Gynecology, Steglitz, Freie Universittit Berlin, 1000 Berlin 45, Hindenburgdamm 30, Federal Republic of Germany
Klinikum
MOLTZ, L. and BECKER, K. (1977): Cribriform polypoid adenomatous (atypical) hyperplasia of the endocervical glands of the uterus under hormonal contraception. Europ. .I. Obstet. Gynec. reprod. Biol., 7/S, 331-336. The occurrence of cribriform adenomatous hyperplasia of the endocervical glands of the uterus was examined in 92 women, in whom punch biopsies of the ecto-endocervical line were taken during the second half of their cycle. Of these, 79 women had taken combined estrogen-progestogen preparations, 9 women had taken progestogens alone, while 14 patients formed a control group. There was a significant difference only between the control group without hormones and the groups treated with hormones. The groups of patients under the various regimes of hormonal treatment displayed a varying percentage of cribriform adenomatous hyperplasia. There was a clear tendency for such lesions to be observed more frequently under the combined type of contraception than under the sequential type. These differences were not, however, significant. A correlation with specific exoge-
nous groups of steroids could not be established. hormonal contraception; atypical hyperplasia
Konikov, 1968) and a number of patients seem to have been treated wrongly - as if they were suffering from cervical carcinoma (Candy and Abell, 1968). It is therefore all the more important for every histopathologist to know about this “histopathology of treatment” (Seidl, 197 1) which, as has been shown in an unpublished study by Moltz, Joschko and Neuser described below, is reversible. Unfortunately only little is known about the incidence of this type of hyperplasia. The histological examination of biopsies and cone sections taken from women with suspect cytological smears or suspect colposcopic findings has shown that the frequency of occurrence of this hyperplasia ranges between 25% and 45% (Gmiir, 1970; Nichols and Fidler, 1971). Joschko and Neuser (1975) were the only ones to examine unselected
Introduction
Since 1967 a number of studies have been conducted on atypical hyperplasia of the endocervical glands of the uterus. An association between these changes and the use of oral contraceptive agents was common to almost all the cases described. The endocervical hyperplasia was all the more striking since it was sometimes combined with epithelial disturbances. Differentiation from adenomatous carcinoma was very difficult in some cases (Bahrmann, 197 1; Taylor, Irey and Norris, 1967; Candy and Abell, 1968; Talbert and Sherry, 1966; Seidl, 1971; Czernobilsky, Kessler and Lancet, 1974; Gall, Bourgeois and Maguire, 1969; Graham, Graham and Hirabayashi, 1968; Haberich, 1970; Kyriakos, Hempson and 331
332
L. Moltz and K. Becker: Endocervical hyperplasia under hormonal contraception
biopsies, and they found the hyperplasia in 32% of their specimens, Since no clarity exists as regards the conditions which give rise to this lesion, we have tried to analyze its incidence in unselected biopsies in relation to the components of different hormonal contraceptives.
TABLE I
Composition
Anacyclin DepoClinovir Eugynon Lyndio12.5
Material and methods
Microgynon Neogynon
an unpublished study by Moltz, Joschko and Neuser from 1970-1972 it was demonstrated that, of 356 women practising contraception with a combined preparation (0.08 mg mestranol and 2.0 mg chlormadinone acetate), 111 displayed cribriform hyperplasia of the endocervical glands. In a control group consisting of 164 women who were not taking hormones, no changes of this nature were observed. Preselection on the basis of, for example, changed cytological or colposcopic findings did not take place. The groups differed neither in respect of their mean age nor in their parity. All 111 patients with a positive histological finding underwent a second histological examination at the earliest 6 mth and at the latest 42 mth later. During this period of time 24 of the women received no more hormones at all, and only 4 of them still displayed hyperplasia at the time of the second examination - one of them even after 42 mth. Of 36 patients who continued to use the same combined preparation, 24 displayed a positive finding at the time of the second histological examination. The other 51 patients were switched to a different combined preparation (0.08 mg mestranol and 1.0 mg norethisterone acetate), but 26 of them still displayed a positive histological finding. According to the x2 test with a 1% probability of error, the association between cribriform hyperplasia of the endocervical glands and the administration of hormones is significant. This hyperplasia is evidently reversible after discontinuation of the hormone therapy. For this paper unselected punch biopsies of the endo-ectocervical line were taken from 92 women in the second half of their menstrual cycle (using sample biopsy forceps, model Aesculap with biopsy insert, Wolff KG). The age of the women varied between 17 and 46 yr (mean age 25.06). Of these 92 women, 14 (mean age 25.0) had not taken any hormones at all for more than 1 yr. The remaining 78 had taken In
Noracyclin Nuriphasic Oraccnal Orgametril Ortho-Novum l/80 Ortho-Novum Ovanon Ovulen Planovin Primolut-Nor Tri-Ervonum
l/SO
of the hormone preparations used
1 .O mg lynestrenol; 0.05 mg ethinylestradiol 150 mg medroxyprogesterone acetate 0.5 mg d-norgestrel; 0.05 mg ethinylestradiol 2.5 mg lynestrenol; 0.05 mg ethinylestradiol 0.15 mg d-norgestrel; 0.03 mg ethinylestradiol 0.25 mg d-norgestrel; 0.05 mg ethinylestradiol 2.5 mg lynestrenol; 0.05 mg ethinylestradiol O/2.5 mg lynestrenol; 0.08/0.075 mg mestranol O.l/l.O mg megestrol acetate; O.l/O.l mg ethinylestradiol 5 mg lynestrenol 1 .O mg norethisterone; 0.08 mg mestrano1 1.0 mg norethisterone;0.05 mg mestranol O/2.5 mg lynestrenol; 0.08/0.075 mg mestranol 1.0 mg etynodiol diacetate; 0.1 mg mestranol 4.0 mg megestrol acetate; 0.05 mg ethinylestradiol 5.0 mg l’lol-ethinyl-19.nortestosterone acetate O.l/l.O mg megestrol acetate; O.l/O.l mg ethinylestradiol
hormones over a period of at least 6 mth immediately prior to the biopsy. Combined-type oral contraceptives were taken by 49 women with a mean age of 26.48 yr (10X Microgynon, 8X Neogynon, 1X Eugynon, 6X Lyndio12.5, 4X Planovin, 4X Noracyclin, 7X Anacyclin, 4X OrthoNovum l/50, 4X Ortho-Novum l/80, 1X Ovulen), sequential type by 20 women with a mean age of 27.07 yr (1X Oraconal, 17X Ovanon, 1X Tri-Ervonum, 1X Nuriphasic), while 9 (mean age 33.31 yr) were treated with progestogens alone for various reasons (5X Depo-Clinovir, 3X Orgametril, 1X Primolut-Nor) (Table I). The specimens were fixed in forrnalin and embedded in paraffin. Each sample was cut serially and the sections were stained with hematoxylin and eosin. The characteristics of the ‘cribriform adenomatous hyperplastic gland tissue’ of the cervix uteri
L. Moltz and K. Becker: Endocervical hyperplasia under hormonal contraception
333
Fig. 1. Normal endocervical glands.
Fig. 2. Cribriform adenomatous hyperplasia of endocervical vacuoles and the hyperplasia of the reserve cells.
glands. Note the reticular formation
of the cells, the intracellular
L. Moltz and K. Becker: Endocervical hyperplasia under hormonal contraception
334
were (Bahrmann, 1971; Seidl, 1971): -loss of original gland structure and cell polarization, the cells forming reticular structures and small alveoli, like a tine sieve; - intracellular vacuoles; - hyperplasia of reserve cells. A specimen was regarded as positive only if the changes were so obvious that there could be no doubt about the finding (Figs. l-2), regardless of their extension to a part of a gland, to a single gland or to several glands. The 1‘I-ketosteroids were determined according to the method of Zimmermann (1955) and the 17.hydroxysteroids according to the method of Few (1961).
to the x2 test the difference between the two groups is significant with a 5% probability of error. These changes were exhibited by 45% of the patients taking the combined type of contraceptive, by 30% of the patients taking the sequential type and by 44% of the patients taking progestogens alone (Table II). There was no significant difference between the treatments - combined or sequential type of contraception or progestogens alone. As regards the estrogen component - ethinylestradiol (EE) in 28 cases with a mean age of 28.4 yr and mestranol (EEME) in 41 cases with a mean age of 23.99 yr - the percentage of positive findings was 39% and 41%, respectively. The difference between these results is not significant. There were no statistically significant differences between the most frequently used progestogens, lynestrenol 35% and d-norgestrel32%. The results did not change even when estrogenic side effects were considered. An elevated adrenocorticoid activity which has been reported previously (Kaiser, 1969) could not be confirmed. The excretion of 17.0~0 and 17.hydroxy corticoids in the urine of 12 patients with cribriform adenomatous hyperplasia did not exceed the normal range.
Results The incidence of cribriform adenomatous hyperplasia in the 78 patients who had taken hormones was 4 l%, regardless of age. Of the 14 women who had not taken hormones for more than 1 yr, only 1 - a patient who had stopped taking i.m. medroxyprogesterone acetate as a contraceptive agent 18 mth before the biopsy - displayed a positive finding. According TABLE II
Frequency treatment
of cribriform
adenomatous
Type of hormone
hyperplasia
of the endocervical glands in relation to the type of hormone
No. of test subjects
Cervical gland hyperplasia of the small alveoli Amount
No hormone therapy Combined preparations Sequential preparations Gestagens only Ethinylestradiol (EE) Mestranol (EEME) Lynestrenol d-Norgestrel EE + d-Norgestrel EEME + Lynestrenol Gestagens with partial estrogenic effect Gestagens without partial estrogenic effect (a) Megestrol acetate (b) Medroxyprogesterone
l Seetext.
14 49 20 9 28 41 38 19 19 32 48 30 6 5
Percentage
Pos.
Neg.
Pos.
Neg.
1’ 22 6 4 11 17 17 6 6 14 21 11 4 1
13 27 14 5 17 24 21 13 13 18 27 19 2 4
7 45 30 44 39 41 35 32 32 44 44 37 67 20
55 70 56 61 59 65 68 68 56 56 63 33 80
93
L. Moltz and K. Becker: Endocervical hyperplosia under hormonal contraception Discussion
Knowledge about histological lesions of the endocervical glands of the uterus relating to hormonal treatment goes back several years. Estrogens (Seidl, Hellmann, Dallenbach-Hellweg, 1969; 1971; Rosenthal, Kistner and Gordon, 1954) as welI as progestogens (Kaiser, 1969; Dallenbach-Hellweg, 1969 ; Dallenbach-Hellweg, Harting, Momber and Thorn, 1971; Dito and Batsakis, 1961; Maqueo, Azuela, Calderon and Goldzieher, 1966) are thought to lead to hyperplastic changes. Lesions similar to cribriform adenomatous hyperplasia were found by Nichols and Fidler (197 1) in 5 patients and by Candy and Abel1 (1968) in 1 patient treated with a progestogen alone and by Hellman et al. (1954) in 12 patients treated with an estrogen alone. Because of the similarity of cribriform adenomatous hyperplasia to alterations of the endocervical glands during pregnancy (Bahrmann, 1971; Seidl, 1971; Nichols and Fidler, 1971; Govan, Black and Sharp, 1969; Hamperl, Kaufmann and Ober, 1954), progestogens were thought to be the cause of such lesions. On the other hand, most of the women under oral contraceptives with this lesion had been taking mestranol in addition to the progestational agent, so this particular estrogenic compound has also been thought to be responsible for this kind of hyperplasia, particularly in view of its proliferative effect (Seidl, 1971). The results obtained in our studies do not support either of these interpretations, nor were any differences observed in respect of the estrogenic, androgenic and/or antiandrogenic partial effects of the various progestational agents. This appears to be true for chlormadinone acetate as well (Joschko and Neuser, 1975). The statistical evaluation of our results is, however, limited by the relatively small number of cases. It must also be borne in mind that, with a biopsy, only a very small specimen of the whole endo-ectocervical zone is examined. In our population of unselected patients there was no indication for larger intervention, e.g. conization. All that can be said is that these changes appeared almost exclusively under treatment with exogenous sex hormones. As already mentioned on p. 332, there are apparently rare cases in which the hyperplasia persists over protracted periods of time - in 1 case for as
335
long as 42 mth. This could quite easily be the explanation for the 1 positive finding in the group of untreated patients. The changes of the endocervical glands during pregnancy are similar but can usually be differentiated from cribriform hyperplasia of the endocervical glands (Seidl, 1971), particularly in late pregnancy. As far as is known, it is not possible to produce an explanation as to why positive findings could only be found in a certain percentage of women under such treatment. Because the histological changes disappear almost completely within 1% yr after discontinuation of the hormonal treatment (see p. 334), and since not a single case of adenomatous carcinoma is so far known to have developed from the cribriform adenomatous hyperplasia, it can be assumed that this is a harmless lesion that is not to be compared with precancerous stages or adenocarcinomata. Confusion with adenocarcinoma is, in any case, only possible in the few cases of greatly pronounced epithelial unrest. No changes of this kind were observed in the present 76 specimens.
References Bahrmann, E. (1971): Polypoide Zervixdriisenhyperplasie am ausseren Muttermund mit Epithehmruhe nach hormonaler Kontrazeption. Zbl. Gytik., 93, 1973. Candy, M. and Abe& R. (1968): Progesteron-induced adenomatous hyperplasia of the uterine cervix. J. Amer. med. Ass., 203, 323. Czernobilsky, B., Kessler, 1. and Lancet, M. (1974): Cervical adenocarcinoma in a woman on long-term contraceptives. Obstet. and Gynec., 4, 517. DaBenbach-Hellweg, G. (1969): Endometrium, Monographie, S. 36. Springer-Verlag, Berlin-Gottingen-Heidelberg. Dallenbach-Hellweg, G., Harting, W., Momber, F. and Thorn, V. (1971): Zytologische und histologische Untersuchungen der Portio und Cervix uteri unter der Einnahme von Ovulationshemmern. Fortschr. Med., 89, 883. Dito, W.R. and Batsakis, J.G. (1961): Norethynodrel-treated endometriosis: a morphologic and histochemical study. Obstet. and Gynec., 18, 1. Few, J.D. (1961): A method for the analysis of urinary 17hydroxycorticosteroids. J. Endocr., 22, 31. Gall, S.A., Bourgeois, C.H. and Maguire, R. (1969): The morphologic effects of oral contraceptive agents on the cervix. J. Amer. med. Ass., 207, 2243. Gmtir, H. (1970): Die Wirkung der Ovulationshemmer auf Portio- und Zervixschleimhaut. Inaugural Dissertation, Medical Faculty, University of Zurich.
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L. Molts and K. Becker: Endocervical hyperplasia under hormonal contraception
Govan, A.D.T., Black, W.P. and Sharp, J.L. (1969): Aberrant glandular polypi of the uterine cervix associated with contraceptive pills: pathology and pathogenesis. J. clin. Path.s22, 84. Graham, J., Graham, R. and Hirabayashi, K. (1968): Reversible ‘cancer’ and the contraceptive pill. O&et. and Gynec., 31, 190. Haberich, M. (1970): Histologischer Beitrag zum sog. Cervixfaktor der Ovulationshemmer, Ref. in: Zbl. allg. Path., 113, 258. Hamperl, H., Kaufmann, C. and Ober, K.G. (1954): Histologische Untersuchungen an der Cervix schwangerer Frauen. Arch. Gyrui:k.,184, 181. Hellmann, L.M., Rosenthal, A.H., Kistner, R.W. and Gordon, R. (1954): Some factors influencing the proliferation of the reserve cells in the human cervix. J. Obstet. Gynec., 67, 899. Joschko, K. and Neuser, D. (1975): ‘Siebartige polypoide Zervixdriisenhyperplasie’ nach oralen Kontrazeptive. Zbl. Gyrufk., 97, 25. Kaiser, R. (1969): Zur Atiologie und Prophylaxe des Endometriumkarzinoms. Geburtsh. u. Frauenheilk., 5, 431.
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