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Metachromasia in the endometrium
METACHROMASIA IN THE ENDOMETRIUM DoNALD
G. McKAY, 1\I.D., BosTox, MAss.
(From the Jlallory Instit-ute of Pathology)
T
HE recent demonstJ·ation of the physiologic importance of ce1·tain acid mucopolysaccharides in tissues has produced increasing interest in these substances. The physiologic and chemical nature of heparin and hyaluronic acid in particular have been studied extensively (Jorpes, 1 Meyer 2 ). It has been shown that metachromasia is one of the properties of these substances and that they may be demonstrated in tissues as a result of this property (\Vislocki, Bunting, and Dempsey 3 ). Several authors have reported the presence of metachromatic substances in human endometrium and decidua (Bensley! Dempsey and \Vislocki,l' Sylven 5 ). It is the purpose of this paper to describe the changes in the metachromatic suLstances in the endometrium during the menstrual cycle and in hyperplasia and carcinoma of the endometrium. Materials and Methods A group of thirty-eight specimens of endometrium were obtained hom uteri removed surgically for various reasons.* The tissues were fixed in a 4 per cent solution of basic lead acetate for twenty-four hours. The deparaffinized sections were stained in a 0.5 per cent aqueous solution of toluidine hlue, according to the methods of Holmgren and Wilander 6 and Holmgren. 7 Alternate sections were incubated for eighteen hours in hyaluronidase since Wislocki, Bunting, and Dempsey 3 have shown that metachromasia due to the presence of hyaluronic acid may be aholished by such treatment.+ The stage of development of each nonpathologic endometrial sample was determined according to the method of Hertig. 8 Twelve of the normal endometria were of the proliferative type and twenty were of the secretory type. One example of fifteen-day endometrium was examined. The date of this endometrium was determined by the fact that there was a recently ruptured follicle in the ovary which showed early luteinization, yet the endometrium did not show evidence of secretion and presented the histologic picture of late proliferative endometrium. Among the secretory endometria were examples of all stages of development up to menstruation. One specimen of endometrium of early pregnancy, three examples of cystic hyperplasia, and one example of secretory l1yperplasia were studied, in addition to two cases of adenocarcinoma of the endometrium. According to Wislocki and Dempsey9 metachromasia in tissues following this method is principally due to mucopolysaccharides. However, in some instances it may be attributed to ribonucleoprotein and in some locations the chemical nature of the substance producing metachromasia is unknown. *~'e wish to express appreciation to Dr. A. T. Hertig of the Free Hospital for Women for placing this material and the facilities of his laboratory at our disposal. tThe hyaluronidase was kindly furnished by Dr. Erwin Schwenck of the Schering Corporation.
875
876
MCKAY
Am.]. Obst. & Gynec. April, 1950
Results rro~trera~;we Endometrium.-.Metaehromasia was present in the intercellular spaces of the stroma of the endometrium in all specimens of this stage of development (Fig. 1). It was present in the superficial one-half or two-thirds Fig. 1.
Fig. 1.-Proliferative endometrium. The metachromatic material is present in an interlaeing network between stromal cells. (X 180.) Fig. ~.-Prolift>rative endometrium. ~everal mast cdls aJ'f> present in the stroma. ( X180.)
ancl was never seen in th e stroma of the basal layer except in the earliest stage immediately following menstruation. Metachromasia was not seen in the epithelial cells of the glands except for a faint reaction in the cytoplasm
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in a few examples of mid-proliferative endometrium. Mast cells were present in all examples of proliferative endometrium (Fig. 2). These were present in moderate numbers and were scattered diffusely throughout the stroma. The metachromasia of the mast cell granules was much more intense than that of the stromal intercellular material. In a few instances the scant secretions in the gland lumina were faintly metachromatic. Fig. 3.
Fig. 4. Fig. 3.-Twenty-day secretory endometrium. The stroma is euematous and there is no intercellular metachromasia. ( X180.) Fig. 4.-Twenty-day secretory endometrium. The secretion in the gland lumina is metachromatic in patches. Parts of the secretion take a dark blue rather than lavender stain. ( X180.)
Early Secretory Endometrium (sixteen to twenty-two days).-The stromal metachromatic substance was not observed in early secretory endometrium (Fig. 3). None of the epithelial cells showed metachromatic staining. Nuclei were blue and the cytoplasm was either clear or blue. Mast cells in most
878
MCKAY
Am. J. Obst. & Gynec. April, 1950
of these specimens were completely absent; one or two mast cells were seen in a few instances. The secretions in gland lumina throughout the secretory phase were prominently metachromatic (Fig. 4). Late Secretory Endometriurn (twenty-three to twenty-six days) .-Intercellular stromal metachromasia was present in these specimens between the predecidual cells immediately beneath the surfact:> t:>pithelinm and around blood Fig. 5.
Fig. 6. Fig. 5.-Early pre g-nancy. Metac hrumatie mate ria l is present between the early decidual eells sharply outlining the cell~. ( X 180.) Fig. 6.--Early pregnancy. Small ann ian;·,, m e tad1romatic g-ra nules are present in the cytoplasm of the early rlecidual cells. ( X 1150.)
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vessels. Mast cells were more numerous in these specimens than in those of early secretory endometrium. In addition, tiny irregular granules were seen in the cytoplasm of the predecidual cells. These were fewer in number than the granules in mast cells and were variable in size rather than uniform as in mast cells. Fig. 7.
Fig. 8.
Fig. 7.-Cystic h yper·pJasia. There is a den se accumulation of metachromatic substance between the strornal cell s. (X 180.) Fig. 8.-Cystic hyperplasia. One gland shows metachromatic secretions a nd a f ew of the epithelial cells contain a similar material. ( X180.)
880
MCKAY
Am.]. Obst. & Gynec. April, 1950
Endomeb·iurn of Early P1·egnancy.-The metachromatic substances in this endometrium were similar in location to those of the late secretory phase but the stromal intercellular material stainrd more intensely (Fig. 5). Also the subintimal region of spiral arterioles gave an intense reaction, which was not noted in endometrial artel'ioles during the cycle. The intracytoplasmic granules which were present in predecidual cells were also seen in the early decidual cells (Fig. 6). 'rhe specimen of "seeretory hyperplasia" was similar to the endometrium of pregnancy. Myometrium.-Metachromasia in the myometrium was confined to the walls of arteries and to the numerous mast cells in the connective tissue immediately surrounding the vessels. There did not appear to be any change in the number of mast eells in this tissue during the menstrual cycle. Cystic Hyperplasia.-These three endometria showed a marked increase in the intercellular stromal metachromasia. There were abundant accumulations around the dilated glands (Fig. 7). Mast cells were present in moderate numbers. One of the striking changes in this type was the appearance of intensely metachromatic material in the epithelial cells of some of the dilated glands (Fig. 8). It was present to a large extent in the basal portion of the epithelial cells next to the basement membrane. In a few cells it was present above the nucleus next to the lumen. The secretions in these gland lumina were strongly metachromatic . .L1denocarcinoma.-In neither of the eases of adenoearcinoma was there metachromatic substance in the epithelial cells of the tumor. These were rapidly growing tumors and contained many solid areas of epithelial cells. In the few strands of connective tissue traversing the tumors were a few scattered mast eells and a faint intercellular metachromasia. Discussion The finding of interct>llular metachromatic substance in the endometrial stroma during the proliferative phase is in accord with the observations of Bensley, 4 Sylven, 5 and Wislocki and Dempsey. 9 'rhe localization in the outer two-thirds is of some interest because it is in this area that the edema of the stroma occurs. We have not seen metachromasia in the hasal one-third except in one case of a very early proliferative endometrium. In contrast to the upper two-thirds, the basal portion does not take part in the cyelic changes resulting in menstruation. Bensley 4 has noted that in the very earliest stage of proliferation there is a slight intercellular edema with no metachromasia. Metachromatic material appears shortly thereafter and is present in increasing amounts at the same time edema is absent during the proliferative phase. In the early secretory phase metaehromasia disappears and edema reaches its peak. In the late stages of secretion, twenty-three to twenty-seven days, edema gradually disappears or diminishes and metachromasia reappears between the predecidual cells. It is present in the ground substance of the decidua eompacta of the placenta (Wislocki and Dempsey9 ). There appears to he a reciprocal relationship between the edema of the stroma of the endometrium and the intercellular metaehromatic substance. Meyer2 states that the acid mueopolysaccharide hyaluronic acid binds water in interstitial spaces. It may be that the intercellular substance in the endometrial stroma behaves in a similar way. The apparent disappearance of metachromasia during early secretion may mean that the mucopolysaccharide is depolyn1erized or disaggregated. Incubation with hyaluronidase did not cause disappearanee of the intercellular metaehromasia although there resulted a slight diminution in the intertsity of the stai11. Therefore hyalrlroni~ acid is probably not the n1ajor
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acid mucopolysaccharide of the intercellular material. Wislocki and Dempsey9 report that hyaluronidase affected none of the metachromasia encountered in the placenta and uterus except that of Wharton's jelly. In late secretory endometrium, that beyond the twenty-third day, in some of the stromal cells surrounding blood vessels, namely predecidual cells, a few metachromatic granules of varying size were seen. Wislocki and Dempsey9 have described similar cells in the decidua vera. These authors concluded that these are decidual cells and not macrophages. It was demonstrated that the metachromasia in the cytoplasm of these cells and of the large true decidual eells was abolished by ribonuclease and it was therefore concluded that this material was ribonucleoprotein. The granules in the predecidual cells of late secretory endometrium are probably ribonucleoprotein particles. The increase in intercellular metachromasia in hyperplastic endometrium is quite striking. There also appears to be an increase in the number of mast cells. It should be noted that the number of mast cells in the endometrium is considerably less than the number in many other types of connective tissue (.Janes and McDonald 10 ). The metachromasia of the cytoplasm of many epithelial cells in hyperplastic endometrium was much more intense than the faint reaction seen in normal proliferative endometrium. Most of the cells which contained it had clear cytoplasm when stained with phloxine-methylene blue. If this intraepithelial substance were ribonucleoprotein, one would expect the cytoplasm to have a basophilic granular appearance when stained with phloxinemethylene blue. However, Atkinson and co-workers 11 have demonstrated basophilic particles in epithelial cells in hyperplastic endometrium and some of the metachromasia in these epithelial cells is probably due to ribonucleoprotein. The secretion of the glands in these hyperplastic endometria was metachromatic and many of the cells were bulging with the same material and appeared to be discharging it into the lumina of the glands. In normal endometrium the scant secretion within the proliferative glands is faintly metachromatic whereas that of the secretory phase is strongly metachromatic. Atkinson and associates 11 have demonstrated that basophilic staining of the secretion of the proliferative phase is abolished by ribonuclease hut that of the secretory phase is not. It seems likely that the secretions of the proliferative phase contain ribonucleoprotein, while the secretion of the secretory phase contains mucus in addition to ribonucleoprotein. Summary
The changes in the metachromatic substance in the endometrium during the menstrual cycle have been described. Intercellular stromal metachromasia is present during the proliferative phase, diminished or absent during the early secretory phase, and reappears between the predecidual cells of the late stages of secretion. There appears to be a reciprocal relation between intercellular stromal metachromasia and edema of the stroma. Mast cells are present during the proliferative phase, diminish in number or are absent in the early stages of secretion and reappear in moderate numbers in late secretion. 'fhey are present in slightly increased numbers in hyperplasia. Metachromatic granules appear in predecidual cells in late secretory endometrium and these are probably ribonucleoprotein particles. Faint metachromasia was observed in the cytoplasm of epithelial cells in a few examples
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MCKAY
Am. J. Obst. & Gynec. April, 1950
of proliferative endometrium. Intense metachromasia was present in the cytoplasm of epithelial cells in hyperplastic endometrium. This probably represents ribonucleoprotein in part but some may be mucopolysaccharide. InflUbation with hyaluronidase failed to abolish any metachromasia in the endometrium. References 1. Jorpes, J. E.: Heparin in the Treatment of Thrombosis, ed. 2, New York and London, 1946, Oxford University Press. 2. Meyer, K.: Physiol. Rev. 27: 335, 1947. 3. Wisloeki, G. B., Bunting, H., and Dempsey, E. W.: Am. J. Anat. 81: 1, 1947. 4. Bensley, 8. H.: Anat. Ree. 60: 93, 1934. 5. Sylven, B.: Cited by Wisloeki and Dempsey.9 6. Holmgren, H., and Wilander, 0.: Ztschr. f .. mikr.-anat. Forsch. 42: 242, 1947. 7. Holmgren, H.: Ztschr. f. mikr.-anat. Forsch. 47: 489, 1940. 8. Hertig, A. T.: Proc. of the Conference on Diagnosis in Sterility, Springfield, Ill., 1945, Charles C Thomas, p. 93. 9. Wislocki, G. B., and Dempsey, E. W.: Am. J. Anat. 83: 1, 1948. 10. Janes, J., and McDonald, .J. R.: Arch. Path. 45: 622, 1948. 11. Atkinson, W. B., Engle, E. T ..• Gusberg, S. B., and Buxton, C. L.: Cancer 2: 132, 194U.
G. McKAY, 1\I.D., BosTox, MAss.
(From the Jlallory Instit-ute of Pathology)
T
HE recent demonstJ·ation of the physiologic importance of ce1·tain acid mucopolysaccharides in tissues has produced increasing interest in these substances. The physiologic and chemical nature of heparin and hyaluronic acid in particular have been studied extensively (Jorpes, 1 Meyer 2 ). It has been shown that metachromasia is one of the properties of these substances and that they may be demonstrated in tissues as a result of this property (\Vislocki, Bunting, and Dempsey 3 ). Several authors have reported the presence of metachromatic substances in human endometrium and decidua (Bensley! Dempsey and \Vislocki,l' Sylven 5 ). It is the purpose of this paper to describe the changes in the metachromatic suLstances in the endometrium during the menstrual cycle and in hyperplasia and carcinoma of the endometrium. Materials and Methods A group of thirty-eight specimens of endometrium were obtained hom uteri removed surgically for various reasons.* The tissues were fixed in a 4 per cent solution of basic lead acetate for twenty-four hours. The deparaffinized sections were stained in a 0.5 per cent aqueous solution of toluidine hlue, according to the methods of Holmgren and Wilander 6 and Holmgren. 7 Alternate sections were incubated for eighteen hours in hyaluronidase since Wislocki, Bunting, and Dempsey 3 have shown that metachromasia due to the presence of hyaluronic acid may be aholished by such treatment.+ The stage of development of each nonpathologic endometrial sample was determined according to the method of Hertig. 8 Twelve of the normal endometria were of the proliferative type and twenty were of the secretory type. One example of fifteen-day endometrium was examined. The date of this endometrium was determined by the fact that there was a recently ruptured follicle in the ovary which showed early luteinization, yet the endometrium did not show evidence of secretion and presented the histologic picture of late proliferative endometrium. Among the secretory endometria were examples of all stages of development up to menstruation. One specimen of endometrium of early pregnancy, three examples of cystic hyperplasia, and one example of secretory l1yperplasia were studied, in addition to two cases of adenocarcinoma of the endometrium. According to Wislocki and Dempsey9 metachromasia in tissues following this method is principally due to mucopolysaccharides. However, in some instances it may be attributed to ribonucleoprotein and in some locations the chemical nature of the substance producing metachromasia is unknown. *~'e wish to express appreciation to Dr. A. T. Hertig of the Free Hospital for Women for placing this material and the facilities of his laboratory at our disposal. tThe hyaluronidase was kindly furnished by Dr. Erwin Schwenck of the Schering Corporation.
875
876
MCKAY
Am.]. Obst. & Gynec. April, 1950
Results rro~trera~;we Endometrium.-.Metaehromasia was present in the intercellular spaces of the stroma of the endometrium in all specimens of this stage of development (Fig. 1). It was present in the superficial one-half or two-thirds Fig. 1.
Fig. 1.-Proliferative endometrium. The metachromatic material is present in an interlaeing network between stromal cells. (X 180.) Fig. ~.-Prolift>rative endometrium. ~everal mast cdls aJ'f> present in the stroma. ( X180.)
ancl was never seen in th e stroma of the basal layer except in the earliest stage immediately following menstruation. Metachromasia was not seen in the epithelial cells of the glands except for a faint reaction in the cytoplasm
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in a few examples of mid-proliferative endometrium. Mast cells were present in all examples of proliferative endometrium (Fig. 2). These were present in moderate numbers and were scattered diffusely throughout the stroma. The metachromasia of the mast cell granules was much more intense than that of the stromal intercellular material. In a few instances the scant secretions in the gland lumina were faintly metachromatic. Fig. 3.
Fig. 4. Fig. 3.-Twenty-day secretory endometrium. The stroma is euematous and there is no intercellular metachromasia. ( X180.) Fig. 4.-Twenty-day secretory endometrium. The secretion in the gland lumina is metachromatic in patches. Parts of the secretion take a dark blue rather than lavender stain. ( X180.)
Early Secretory Endometrium (sixteen to twenty-two days).-The stromal metachromatic substance was not observed in early secretory endometrium (Fig. 3). None of the epithelial cells showed metachromatic staining. Nuclei were blue and the cytoplasm was either clear or blue. Mast cells in most
878
MCKAY
Am. J. Obst. & Gynec. April, 1950
of these specimens were completely absent; one or two mast cells were seen in a few instances. The secretions in gland lumina throughout the secretory phase were prominently metachromatic (Fig. 4). Late Secretory Endometriurn (twenty-three to twenty-six days) .-Intercellular stromal metachromasia was present in these specimens between the predecidual cells immediately beneath the surfact:> t:>pithelinm and around blood Fig. 5.
Fig. 6. Fig. 5.-Early pre g-nancy. Metac hrumatie mate ria l is present between the early decidual eells sharply outlining the cell~. ( X 180.) Fig. 6.--Early pregnancy. Small ann ian;·,, m e tad1romatic g-ra nules are present in the cytoplasm of the early rlecidual cells. ( X 1150.)
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vessels. Mast cells were more numerous in these specimens than in those of early secretory endometrium. In addition, tiny irregular granules were seen in the cytoplasm of the predecidual cells. These were fewer in number than the granules in mast cells and were variable in size rather than uniform as in mast cells. Fig. 7.
Fig. 8.
Fig. 7.-Cystic h yper·pJasia. There is a den se accumulation of metachromatic substance between the strornal cell s. (X 180.) Fig. 8.-Cystic hyperplasia. One gland shows metachromatic secretions a nd a f ew of the epithelial cells contain a similar material. ( X180.)
880
MCKAY
Am.]. Obst. & Gynec. April, 1950
Endomeb·iurn of Early P1·egnancy.-The metachromatic substances in this endometrium were similar in location to those of the late secretory phase but the stromal intercellular material stainrd more intensely (Fig. 5). Also the subintimal region of spiral arterioles gave an intense reaction, which was not noted in endometrial artel'ioles during the cycle. The intracytoplasmic granules which were present in predecidual cells were also seen in the early decidual cells (Fig. 6). 'rhe specimen of "seeretory hyperplasia" was similar to the endometrium of pregnancy. Myometrium.-Metachromasia in the myometrium was confined to the walls of arteries and to the numerous mast cells in the connective tissue immediately surrounding the vessels. There did not appear to be any change in the number of mast eells in this tissue during the menstrual cycle. Cystic Hyperplasia.-These three endometria showed a marked increase in the intercellular stromal metachromasia. There were abundant accumulations around the dilated glands (Fig. 7). Mast cells were present in moderate numbers. One of the striking changes in this type was the appearance of intensely metachromatic material in the epithelial cells of some of the dilated glands (Fig. 8). It was present to a large extent in the basal portion of the epithelial cells next to the basement membrane. In a few cells it was present above the nucleus next to the lumen. The secretions in these gland lumina were strongly metachromatic . .L1denocarcinoma.-In neither of the eases of adenoearcinoma was there metachromatic substance in the epithelial cells of the tumor. These were rapidly growing tumors and contained many solid areas of epithelial cells. In the few strands of connective tissue traversing the tumors were a few scattered mast eells and a faint intercellular metachromasia. Discussion The finding of interct>llular metachromatic substance in the endometrial stroma during the proliferative phase is in accord with the observations of Bensley, 4 Sylven, 5 and Wislocki and Dempsey. 9 'rhe localization in the outer two-thirds is of some interest because it is in this area that the edema of the stroma occurs. We have not seen metachromasia in the hasal one-third except in one case of a very early proliferative endometrium. In contrast to the upper two-thirds, the basal portion does not take part in the cyelic changes resulting in menstruation. Bensley 4 has noted that in the very earliest stage of proliferation there is a slight intercellular edema with no metachromasia. Metachromatic material appears shortly thereafter and is present in increasing amounts at the same time edema is absent during the proliferative phase. In the early secretory phase metaehromasia disappears and edema reaches its peak. In the late stages of secretion, twenty-three to twenty-seven days, edema gradually disappears or diminishes and metachromasia reappears between the predecidual cells. It is present in the ground substance of the decidua eompacta of the placenta (Wislocki and Dempsey9 ). There appears to he a reciprocal relationship between the edema of the stroma of the endometrium and the intercellular metaehromatic substance. Meyer2 states that the acid mueopolysaccharide hyaluronic acid binds water in interstitial spaces. It may be that the intercellular substance in the endometrial stroma behaves in a similar way. The apparent disappearance of metachromasia during early secretion may mean that the mucopolysaccharide is depolyn1erized or disaggregated. Incubation with hyaluronidase did not cause disappearanee of the intercellular metaehromasia although there resulted a slight diminution in the intertsity of the stai11. Therefore hyalrlroni~ acid is probably not the n1ajor
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881
acid mucopolysaccharide of the intercellular material. Wislocki and Dempsey9 report that hyaluronidase affected none of the metachromasia encountered in the placenta and uterus except that of Wharton's jelly. In late secretory endometrium, that beyond the twenty-third day, in some of the stromal cells surrounding blood vessels, namely predecidual cells, a few metachromatic granules of varying size were seen. Wislocki and Dempsey9 have described similar cells in the decidua vera. These authors concluded that these are decidual cells and not macrophages. It was demonstrated that the metachromasia in the cytoplasm of these cells and of the large true decidual eells was abolished by ribonuclease and it was therefore concluded that this material was ribonucleoprotein. The granules in the predecidual cells of late secretory endometrium are probably ribonucleoprotein particles. The increase in intercellular metachromasia in hyperplastic endometrium is quite striking. There also appears to be an increase in the number of mast cells. It should be noted that the number of mast cells in the endometrium is considerably less than the number in many other types of connective tissue (.Janes and McDonald 10 ). The metachromasia of the cytoplasm of many epithelial cells in hyperplastic endometrium was much more intense than the faint reaction seen in normal proliferative endometrium. Most of the cells which contained it had clear cytoplasm when stained with phloxine-methylene blue. If this intraepithelial substance were ribonucleoprotein, one would expect the cytoplasm to have a basophilic granular appearance when stained with phloxinemethylene blue. However, Atkinson and co-workers 11 have demonstrated basophilic particles in epithelial cells in hyperplastic endometrium and some of the metachromasia in these epithelial cells is probably due to ribonucleoprotein. The secretion of the glands in these hyperplastic endometria was metachromatic and many of the cells were bulging with the same material and appeared to be discharging it into the lumina of the glands. In normal endometrium the scant secretion within the proliferative glands is faintly metachromatic whereas that of the secretory phase is strongly metachromatic. Atkinson and associates 11 have demonstrated that basophilic staining of the secretion of the proliferative phase is abolished by ribonuclease hut that of the secretory phase is not. It seems likely that the secretions of the proliferative phase contain ribonucleoprotein, while the secretion of the secretory phase contains mucus in addition to ribonucleoprotein. Summary
The changes in the metachromatic substance in the endometrium during the menstrual cycle have been described. Intercellular stromal metachromasia is present during the proliferative phase, diminished or absent during the early secretory phase, and reappears between the predecidual cells of the late stages of secretion. There appears to be a reciprocal relation between intercellular stromal metachromasia and edema of the stroma. Mast cells are present during the proliferative phase, diminish in number or are absent in the early stages of secretion and reappear in moderate numbers in late secretion. 'fhey are present in slightly increased numbers in hyperplasia. Metachromatic granules appear in predecidual cells in late secretory endometrium and these are probably ribonucleoprotein particles. Faint metachromasia was observed in the cytoplasm of epithelial cells in a few examples
882
MCKAY
Am. J. Obst. & Gynec. April, 1950
of proliferative endometrium. Intense metachromasia was present in the cytoplasm of epithelial cells in hyperplastic endometrium. This probably represents ribonucleoprotein in part but some may be mucopolysaccharide. InflUbation with hyaluronidase failed to abolish any metachromasia in the endometrium. References 1. Jorpes, J. E.: Heparin in the Treatment of Thrombosis, ed. 2, New York and London, 1946, Oxford University Press. 2. Meyer, K.: Physiol. Rev. 27: 335, 1947. 3. Wisloeki, G. B., Bunting, H., and Dempsey, E. W.: Am. J. Anat. 81: 1, 1947. 4. Bensley, 8. H.: Anat. Ree. 60: 93, 1934. 5. Sylven, B.: Cited by Wisloeki and Dempsey.9 6. Holmgren, H., and Wilander, 0.: Ztschr. f .. mikr.-anat. Forsch. 42: 242, 1947. 7. Holmgren, H.: Ztschr. f. mikr.-anat. Forsch. 47: 489, 1940. 8. Hertig, A. T.: Proc. of the Conference on Diagnosis in Sterility, Springfield, Ill., 1945, Charles C Thomas, p. 93. 9. Wislocki, G. B., and Dempsey, E. W.: Am. J. Anat. 83: 1, 1948. 10. Janes, J., and McDonald, .J. R.: Arch. Path. 45: 622, 1948. 11. Atkinson, W. B., Engle, E. T ..• Gusberg, S. B., and Buxton, C. L.: Cancer 2: 132, 194U.