Acta Obstet Gynecol Scand 58:283-285, 1979
MENORRHAGIA, DIFFUSE MYOMETRIAL HYPERTROPHY AND THE INTRAUTERINE CONTRACEPTIVE DEVICE: A REPORT OF FOURTEEN CASES Louis H . HonorC From the Department of Pathology, Vancouver General Hospital, Vancouver, B. C., Canada
Abstract. Fourteen uteri, removed for IUD-associated menorrhagia, were studied. Twelve of these IUD-bearing uteri showed pure diffuse myometrial hypertrophy; the other two uteri were enlarged as a result of multiple leiomyomas in one case and extensive deep adenomyosis in the other. The incidence of pure myometrial hypertrophy in the IUD group Was far in excess Of that observed in a control non-IUDbearing menorrhagia series, where leiomyomas and/or deep adenomyosis were mostly responsible for the uterine enlargement.
cell and broadening of the muscle bands, as seen microscopica~~y~ The present study was confined to menorrhagia associated with benign uterine enlargement (trimmed uterine weight > 125 grams) and its main purpose was to determine whether a similar distribution of pathologic changes, underlying the uterine enlargement, was present in the IUD group as compared with the non-IUD group.
The obstetric and gynecologic complications of the intrauterine contraceptive device (IUD) have been extensively documented (5, 6 , 9, 13, 15, 16). Abnormal uterine bleeding, especially menorrhagia, remains the commonest cause of IUD intolerance and removal within the first few months of insertion and at least three factors have been identified as etiologically significant, i.e. local pressure necrosis with microulcerations (11); vascular congestion, platelet thrombi, and microhemorrhages in the endometrium not in contact with the IUD (1); increased levels of plasminogen activator in the endometrium and superficial myometrium (12). Review of the major publications on the IUD reveals no mention of menorrhagia related to diffuse uterine enlargement. The problem of uterine enlargement is bedevilled by the lack of agreement as to what constitutes the upper limit of a ‘‘normal’’ parous uterus. Various values have been mentioned ranging from 117 to 125 (2, 10, 14) and we have adopted 125 grams as enlarged, regardless of the clinical associations. This purely anatomic diagnosis (10) is justified by the presence of one or more of the following findings: symmetric globular enlargment of the corpus, enlongation and enlargement of the cervix, diffuse or localized (subserosal or submucosal) thickening of the myometrium, which often exceeds 2 cms in thickness, and hypertrophy of the individual myometrial
MATERIAL AND METHODS The author personally studied a total of 384 uteri removed for menorrhagia. For this present study the control group (women not wearing the IUD at the time of operation) consisted of 254 uteri, exceeding 125 grams in weight and satisfying the criteria for benign enlargement; these uteri were aged 26 to 54 years. removed from The IUD group consisted of 19 uteri, with 14 exceeding 125 grams in weight and satisfying the critera for benign enlargement. These uteri came from women aged 29 to 48 years. The IUD’s used were the Dalkon Shield and Lippes’ Loop. In a pilot study it was noted that the incidence of pure myometrial hypertrophy fell above a uterine weight of 150 gram, whereas leiomyomas and deep adenomyosis, singly or in combination, assumed greater importance. For this reason the data were analysed using 150 grams as a dividing line.
RESULTS The analysis of the control series is summarized in table I. These uteri ranged in weight from 125 to 1 090 grams, with the majority lying between 130 to 300 grams and these weights bore no relationship to parity. A lower percentage of these uteri (34.65 per cent) weighed less than 150 grams: of these 57.95 per cent showed pure myometrial hypertrophy and 42.05 per cent showed myometrial lesions, i.e. leiomyomas and/or deep adenomyosis. Among the uteri weighing over 150 grams, pure myometrial hypertrophy was Acla Ob.rrel Gynecol Scand 58 (1979)
284
Louis H. Honor6
Table I. Control menorrhagia group without IUD. Number Incidence
of cases per cent fraction Uteri weighing under 150 g Uteri under 150 g with pure myometrial hypertrophy Uteri under 150 g with leiomyomas and/or deep
adenomyosis
Uteri weighing over 150 g Uteri over 150 g with pure
myometrial hypertrophy Uteri over 150 g with leiomyomas and/or deep adenomyosis Total
88
34.65
88/254
51
57.95
51/88
37
42.05
37/88
166
65.35
166/254
35
21.08
35/166
131
78.92
131/166
-
-
254
seen in only 21.08 per cent while uteri with leiomyomas and/or deep adenomyosis predominated (78.92 per cent). In the much smaller IUD series (table 11) only four uteri, ranging from 127 to 135 grams, weighed under 150 grams (28.42 per cent) and all showed myometrial hypertrophy. The remaining ten uteri (71.58 per cent) ranged from 152 to 296 grams (mean weight = 178.9 grams), and eight of these uteri displayed pure myometrial hypertrophy, while in one of the remaining two cases uterine enlargement was due to leiomyomas and in the other to diffuse adenomyosis. Comparison of the incidence of pure myometrial hypertrophy in these two series demonstrated a striking preponderance of this lesion in IUD series in both categories of uteri examined but especially in the uteri weighing over 150 grams. Among the uteri weighing under 150 grams, the incidence of pure myometrial hypertrophy was 57.95 per cent in the control series and 100 per cent in the IUD series; among the uteri weighing over 150 grams, the incidence of myometrial hypertrophy was 21.08 per cent in the control series and 80 per cent in the IUD series.
DISCUSSION The incidence of uterine enlargement due to pure myometrial hypertrophy in our IUD series is significantly increased, as compared with the control series but the question arises as to whether the myometrial hypertrophy is causally related to the menorrhagia. Some causes of abnormal uterine bleeding can be excluded, such as endometrial hyperplasia, polyp or Acta Obstet GynecoI Scand 58 (1979)
carcinoma, postabortal metropathy, nonspecific endometritis, severe superficial adenomyosis, and submucosal leiomyomas. Extensive histologic study showed only occasional minute foci of pressure necrosis in areas of contact as described by Moyer et al. (1 1). We cannot rule out microaneurysms of the endometrium not in contact with the IUD (l), as no ultrastructural studies were done; nor can we exclude an excess of plasminogen activator in the endomtrium and superficial myometrium (12), as no assay of this substance was undertaken. The only significant factor therefore remains the diffuse myometrial hypertrophy, which we consider responsible for the menorrhagia, as suggested by many authors in the past (4,7, 17). It is conceivable, though unproven, that an abnormally thick myometrium is unable to promote adequate hemostasis during menstruation. The mechanism of myometrial hypertrophy in these IUDbearing uteri is obscure but is clearly not related to outflow obstruction, associated pregnancy, or obvious hyperestrinism, since these women showed no tendency to endometrial hyperplasia. Nor can the myometrial hypertrophy be attributed to chronic overstretch of the uterus by oversized devices, which had been tolerated for up to three years without significant discomfort, and grossly there was no undue expansion of the uterine cavity or burrowing of the IUD into the myometrium. The most likely mechanism is related to locally released prostaglandins by the IUD, as shown experimentally in the rat uterine horn (3). The rarity of significant myometrial hypertrophy with the IUD may reflect the extreme variability of response of the endometrium to the IUD in terms of local prostaglandin release (8); these women may release unusually large amounts of PGFb, which is a potent stimulator
Table 11. Menorrhagia associated with IUD. Number Incidence of cases per cent fraction Uteri weighing under 150 g Uteri under 150 g with pure
4
myometrial hypertrophy
4
Uteri weighing over 150 g Uteri over 150 g with pure
10
myometrial hypertrophy 8 Uteri over 150 g with adeno2 myosis/leiomyomas Total
14
28.42 100
4/14 4/4
71.58
1&V14
80
8/10
20
-
2/10
-
IUD and dqfuse myometrial hyperplasia
of the myometrium. This chronic excess of PGF2,, though inadequate to cause significant spasm and clinical discomfort, may lead to progressive myometrial hypertrophy over a variable period of time. Finally, most of these uteri also showed cervical elongation (length > 3.5 cm) and concentric enlargement (diameter of cervical cylinder > 3 cm). No explanation of this phenomenon is available but it is possible that the string of the IUD in the canal may also locally release prostaglandins, which may have an effect on the submucosal fibrovascular tissues and the myocervix. It might be rewarding to pay more attention to the cervix in studying the contraceptive action of the IUD.
REFERENCES 1. Ancla, M., DeBrux, J. & Simon, P.: Aneurysmal mic-
rothrombosis associated with intrauterine devices in the human endometrium. An electron-microscopic study. Lab Invest 17:61, 1967. 2. Armed Forces Institute of Pathology: The Autopsy, Washington, D.C., p. 41, 1951. 3. Chaudhuri, G.: Influence of Indomethacin, an inhibitor of prostaglandin synthesis, on IUD-mediated increased mobility and hypertrophy of the rat uterine horn. In Analysis of Intrauterine Contraception (ed. Hefnawi, F. and Segal, S. J.), p. 447-480. North Holland Publishing Co, Amsterdam, Oxford-American Elsevier Publishing Company Inc, New York, 1975. 4. Curtis, A. H.: Hypertrophy of the uterus. Am J Obstet Gynecol50:748, 1945. 5 . Hallatt, J. G.: Ectopic pregnancy associated with the intrauterine device. Am J Obstet Gynecol 125:754, 1976. 6. Hefnawi, F. & Segal, S. J.: Analysis of intrauterine contraception. North Holland Publishing Company, Amsterdam, Oxford-American Elsevier Publishing Company, New York, pp. 333-476, 1975.
285
7. Hillier, H.: Micromyomas of the uterus with severe
menorrhagia: a syndrome. Am J Obstet Gynecol 87:163, 1963.
8. Hillier, I(. & Kasonde, J. M.: Prostaglandin E and F concentrations in human endometrium after insertion of intrauterine contraceptive device. Lancet 1:15, 1976. 9. Kahn, H. S. & Tyler, C. W.: Mortality associated with the use of intrauterine devices. JAMA 234:57, 1976. 10. Lewis, P. L., Lee, A. B. H. & Easler, R. E.: Myometrial hypertrophy. A clinical pathologic study and review of the literature. Am J Obstet Gynecol. 84:1032, 1962. 11. Moyer, D. L., Mishell, D. R., Jr. & Bell, J.: Reactions of the human endometrium to the intrauterine device I: correlation of the endometrial histology and the bacterial environment of the uterus following short term insertion of the IUD. Am J Obstet Gynecol106:7, 1970. 12. Poon, C. H., Shaw, S. T., Jr. &Moyer, D. L.: Protease activity in uterine fluid and tissue associated with intrauterine devices. Paper presented at the 21st Annual Meeting of the Pacific Coast Fertility Society, October, 1973, Palm Springs, California. 13. Roland, M.: The Response to Contraception. W. B. Saunders Company, Philadelphia, London, Toronto, p. 111-132, 1973. 14. Saphir, 0.:Autopsy Diagnosis and Technique, 2nd Edition, Paul B. Hoeber Inc., New York, p. 374, 1946. 15. Weekes, L. R.: Complications of intrauterine contraceptive devices. J Ntl Med Assoc 67:1, 1975. 16. Wheeler, R. G., Duncan, G. W. & Speidel, J. J.: In-
trauterine Devices: Development, Evaluation and Program, Academic Press, New York, San Francisco, London, passim, 1974. 17. Williams, J. T.: & Kinney, T. D.: Myometrial hypertrophy (so-called fibrosis uteri). Am J Obstet Gynecol 47:380, 1947.
Submitted for publication October 28, 1977 Louis Honor6 Department of Laboratories Grace General Hospital St John’s, Newfoundland Canada
Acta Obstet Gynecol Scand 58 (1979)
MENORRHAGIA, DIFFUSE MYOMETRIAL HYPERTROPHY AND THE INTRAUTERINE CONTRACEPTIVE DEVICE: A REPORT OF FOURTEEN CASES Louis H . HonorC From the Department of Pathology, Vancouver General Hospital, Vancouver, B. C., Canada
Abstract. Fourteen uteri, removed for IUD-associated menorrhagia, were studied. Twelve of these IUD-bearing uteri showed pure diffuse myometrial hypertrophy; the other two uteri were enlarged as a result of multiple leiomyomas in one case and extensive deep adenomyosis in the other. The incidence of pure myometrial hypertrophy in the IUD group Was far in excess Of that observed in a control non-IUDbearing menorrhagia series, where leiomyomas and/or deep adenomyosis were mostly responsible for the uterine enlargement.
cell and broadening of the muscle bands, as seen microscopica~~y~ The present study was confined to menorrhagia associated with benign uterine enlargement (trimmed uterine weight > 125 grams) and its main purpose was to determine whether a similar distribution of pathologic changes, underlying the uterine enlargement, was present in the IUD group as compared with the non-IUD group.
The obstetric and gynecologic complications of the intrauterine contraceptive device (IUD) have been extensively documented (5, 6 , 9, 13, 15, 16). Abnormal uterine bleeding, especially menorrhagia, remains the commonest cause of IUD intolerance and removal within the first few months of insertion and at least three factors have been identified as etiologically significant, i.e. local pressure necrosis with microulcerations (11); vascular congestion, platelet thrombi, and microhemorrhages in the endometrium not in contact with the IUD (1); increased levels of plasminogen activator in the endometrium and superficial myometrium (12). Review of the major publications on the IUD reveals no mention of menorrhagia related to diffuse uterine enlargement. The problem of uterine enlargement is bedevilled by the lack of agreement as to what constitutes the upper limit of a ‘‘normal’’ parous uterus. Various values have been mentioned ranging from 117 to 125 (2, 10, 14) and we have adopted 125 grams as enlarged, regardless of the clinical associations. This purely anatomic diagnosis (10) is justified by the presence of one or more of the following findings: symmetric globular enlargment of the corpus, enlongation and enlargement of the cervix, diffuse or localized (subserosal or submucosal) thickening of the myometrium, which often exceeds 2 cms in thickness, and hypertrophy of the individual myometrial
MATERIAL AND METHODS The author personally studied a total of 384 uteri removed for menorrhagia. For this present study the control group (women not wearing the IUD at the time of operation) consisted of 254 uteri, exceeding 125 grams in weight and satisfying the criteria for benign enlargement; these uteri were aged 26 to 54 years. removed from The IUD group consisted of 19 uteri, with 14 exceeding 125 grams in weight and satisfying the critera for benign enlargement. These uteri came from women aged 29 to 48 years. The IUD’s used were the Dalkon Shield and Lippes’ Loop. In a pilot study it was noted that the incidence of pure myometrial hypertrophy fell above a uterine weight of 150 gram, whereas leiomyomas and deep adenomyosis, singly or in combination, assumed greater importance. For this reason the data were analysed using 150 grams as a dividing line.
RESULTS The analysis of the control series is summarized in table I. These uteri ranged in weight from 125 to 1 090 grams, with the majority lying between 130 to 300 grams and these weights bore no relationship to parity. A lower percentage of these uteri (34.65 per cent) weighed less than 150 grams: of these 57.95 per cent showed pure myometrial hypertrophy and 42.05 per cent showed myometrial lesions, i.e. leiomyomas and/or deep adenomyosis. Among the uteri weighing over 150 grams, pure myometrial hypertrophy was Acla Ob.rrel Gynecol Scand 58 (1979)
284
Louis H. Honor6
Table I. Control menorrhagia group without IUD. Number Incidence
of cases per cent fraction Uteri weighing under 150 g Uteri under 150 g with pure myometrial hypertrophy Uteri under 150 g with leiomyomas and/or deep
adenomyosis
Uteri weighing over 150 g Uteri over 150 g with pure
myometrial hypertrophy Uteri over 150 g with leiomyomas and/or deep adenomyosis Total
88
34.65
88/254
51
57.95
51/88
37
42.05
37/88
166
65.35
166/254
35
21.08
35/166
131
78.92
131/166
-
-
254
seen in only 21.08 per cent while uteri with leiomyomas and/or deep adenomyosis predominated (78.92 per cent). In the much smaller IUD series (table 11) only four uteri, ranging from 127 to 135 grams, weighed under 150 grams (28.42 per cent) and all showed myometrial hypertrophy. The remaining ten uteri (71.58 per cent) ranged from 152 to 296 grams (mean weight = 178.9 grams), and eight of these uteri displayed pure myometrial hypertrophy, while in one of the remaining two cases uterine enlargement was due to leiomyomas and in the other to diffuse adenomyosis. Comparison of the incidence of pure myometrial hypertrophy in these two series demonstrated a striking preponderance of this lesion in IUD series in both categories of uteri examined but especially in the uteri weighing over 150 grams. Among the uteri weighing under 150 grams, the incidence of pure myometrial hypertrophy was 57.95 per cent in the control series and 100 per cent in the IUD series; among the uteri weighing over 150 grams, the incidence of myometrial hypertrophy was 21.08 per cent in the control series and 80 per cent in the IUD series.
DISCUSSION The incidence of uterine enlargement due to pure myometrial hypertrophy in our IUD series is significantly increased, as compared with the control series but the question arises as to whether the myometrial hypertrophy is causally related to the menorrhagia. Some causes of abnormal uterine bleeding can be excluded, such as endometrial hyperplasia, polyp or Acta Obstet GynecoI Scand 58 (1979)
carcinoma, postabortal metropathy, nonspecific endometritis, severe superficial adenomyosis, and submucosal leiomyomas. Extensive histologic study showed only occasional minute foci of pressure necrosis in areas of contact as described by Moyer et al. (1 1). We cannot rule out microaneurysms of the endometrium not in contact with the IUD (l), as no ultrastructural studies were done; nor can we exclude an excess of plasminogen activator in the endomtrium and superficial myometrium (12), as no assay of this substance was undertaken. The only significant factor therefore remains the diffuse myometrial hypertrophy, which we consider responsible for the menorrhagia, as suggested by many authors in the past (4,7, 17). It is conceivable, though unproven, that an abnormally thick myometrium is unable to promote adequate hemostasis during menstruation. The mechanism of myometrial hypertrophy in these IUDbearing uteri is obscure but is clearly not related to outflow obstruction, associated pregnancy, or obvious hyperestrinism, since these women showed no tendency to endometrial hyperplasia. Nor can the myometrial hypertrophy be attributed to chronic overstretch of the uterus by oversized devices, which had been tolerated for up to three years without significant discomfort, and grossly there was no undue expansion of the uterine cavity or burrowing of the IUD into the myometrium. The most likely mechanism is related to locally released prostaglandins by the IUD, as shown experimentally in the rat uterine horn (3). The rarity of significant myometrial hypertrophy with the IUD may reflect the extreme variability of response of the endometrium to the IUD in terms of local prostaglandin release (8); these women may release unusually large amounts of PGFb, which is a potent stimulator
Table 11. Menorrhagia associated with IUD. Number Incidence of cases per cent fraction Uteri weighing under 150 g Uteri under 150 g with pure
4
myometrial hypertrophy
4
Uteri weighing over 150 g Uteri over 150 g with pure
10
myometrial hypertrophy 8 Uteri over 150 g with adeno2 myosis/leiomyomas Total
14
28.42 100
4/14 4/4
71.58
1&V14
80
8/10
20
-
2/10
-
IUD and dqfuse myometrial hyperplasia
of the myometrium. This chronic excess of PGF2,, though inadequate to cause significant spasm and clinical discomfort, may lead to progressive myometrial hypertrophy over a variable period of time. Finally, most of these uteri also showed cervical elongation (length > 3.5 cm) and concentric enlargement (diameter of cervical cylinder > 3 cm). No explanation of this phenomenon is available but it is possible that the string of the IUD in the canal may also locally release prostaglandins, which may have an effect on the submucosal fibrovascular tissues and the myocervix. It might be rewarding to pay more attention to the cervix in studying the contraceptive action of the IUD.
REFERENCES 1. Ancla, M., DeBrux, J. & Simon, P.: Aneurysmal mic-
rothrombosis associated with intrauterine devices in the human endometrium. An electron-microscopic study. Lab Invest 17:61, 1967. 2. Armed Forces Institute of Pathology: The Autopsy, Washington, D.C., p. 41, 1951. 3. Chaudhuri, G.: Influence of Indomethacin, an inhibitor of prostaglandin synthesis, on IUD-mediated increased mobility and hypertrophy of the rat uterine horn. In Analysis of Intrauterine Contraception (ed. Hefnawi, F. and Segal, S. J.), p. 447-480. North Holland Publishing Co, Amsterdam, Oxford-American Elsevier Publishing Company Inc, New York, 1975. 4. Curtis, A. H.: Hypertrophy of the uterus. Am J Obstet Gynecol50:748, 1945. 5 . Hallatt, J. G.: Ectopic pregnancy associated with the intrauterine device. Am J Obstet Gynecol 125:754, 1976. 6. Hefnawi, F. & Segal, S. J.: Analysis of intrauterine contraception. North Holland Publishing Company, Amsterdam, Oxford-American Elsevier Publishing Company, New York, pp. 333-476, 1975.
285
7. Hillier, H.: Micromyomas of the uterus with severe
menorrhagia: a syndrome. Am J Obstet Gynecol 87:163, 1963.
8. Hillier, I(. & Kasonde, J. M.: Prostaglandin E and F concentrations in human endometrium after insertion of intrauterine contraceptive device. Lancet 1:15, 1976. 9. Kahn, H. S. & Tyler, C. W.: Mortality associated with the use of intrauterine devices. JAMA 234:57, 1976. 10. Lewis, P. L., Lee, A. B. H. & Easler, R. E.: Myometrial hypertrophy. A clinical pathologic study and review of the literature. Am J Obstet Gynecol. 84:1032, 1962. 11. Moyer, D. L., Mishell, D. R., Jr. & Bell, J.: Reactions of the human endometrium to the intrauterine device I: correlation of the endometrial histology and the bacterial environment of the uterus following short term insertion of the IUD. Am J Obstet Gynecol106:7, 1970. 12. Poon, C. H., Shaw, S. T., Jr. &Moyer, D. L.: Protease activity in uterine fluid and tissue associated with intrauterine devices. Paper presented at the 21st Annual Meeting of the Pacific Coast Fertility Society, October, 1973, Palm Springs, California. 13. Roland, M.: The Response to Contraception. W. B. Saunders Company, Philadelphia, London, Toronto, p. 111-132, 1973. 14. Saphir, 0.:Autopsy Diagnosis and Technique, 2nd Edition, Paul B. Hoeber Inc., New York, p. 374, 1946. 15. Weekes, L. R.: Complications of intrauterine contraceptive devices. J Ntl Med Assoc 67:1, 1975. 16. Wheeler, R. G., Duncan, G. W. & Speidel, J. J.: In-
trauterine Devices: Development, Evaluation and Program, Academic Press, New York, San Francisco, London, passim, 1974. 17. Williams, J. T.: & Kinney, T. D.: Myometrial hypertrophy (so-called fibrosis uteri). Am J Obstet Gynecol 47:380, 1947.
Submitted for publication October 28, 1977 Louis Honor6 Department of Laboratories Grace General Hospital St John’s, Newfoundland Canada
Acta Obstet Gynecol Scand 58 (1979)
