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Newer concepts of menstruation
NEWER
CONCEPTS
OF MENSTRUATION”
IRWIN H. KAISER; M.D., BALTIMORE, M.D. (From
the Department Department
of
Embryology, Obstetrics,
of
Carnegie Institution of Washington. Sinai Hospital of Raltimore)
and
the
LEEDING is the most striking feature of the menstrual process. A large part of the clinical and laboratory study of menstruation in the past two decades has, therefore, b,een directed toward the blood vessels of the endometrium. On the basis of this work, an explanation of cyclic uterine bleeding as a consequence of alterations of the coiled arterioles of the endometrium has gained widespread acceptance. Unfortunately, this explanation has been carried so far that it now fits only certain special cases. The most recent laborat,ory findings as well as many familiar clinical observations require a return to a more general physiologic concept of menstruation as a result of withdrawal of metabolic support of the endometrium.
B
It has been known for some time that the vasculature of the endometrium undergoes cyclic changes along with the glands and stroma (Saito,22 DarorP). The basal arterioles, situated in the deepest portion of the endometrium, are not shed in the menstrual, discharge and do not participate in these cyclic changes. The coiled arterioles, which eventually reach almost to the superficial epithelium, Just after the completion of bleeding, the manifest remarkable alterations. endometrium is shallow and the coiled arterioles have but a few loops. As the follicular phase proceeds, the endometrium thickens and the arterioles add loops and lengthen, remaining confined to the inner half of the mucous membrane. If ovulation fails to occur and growth continues, due to continued estrogen stimulation, vessels such as those in Figs. 1, 6, and 7 develop. If, however, a functioning corpus luteum is formed, the coiled arterioles become much more complex and extend further out into the endometrium as the secretory changes of the glands and stroma take place. With the approach of menstruation, the contortion and buckling of the vessels become extreme, as in Figs. 2, 8, and 9. The distal portion of the vessel is lost thereafter in the menstrual discharge. Markeel has added greatly to the understanding of these changes by describing them as they take place in endometrium transplanted to the anterior chamber of a rhesus monkey’s eye. He observed that the bulk of endometrial bleeding is arteriolar in origin and that, therefore, the coiled arterioles control the amount and rate of menstrual hemorrhage. The explanation of menstruation as a consequence of vascular changes is based primarily on these observations In the years that have followed the publication of these findings, so many interpretations of their meaning, all of them similar, have been made in textbook and monograph discussions of menstruation that it would be unfair to cite any one author’s exposition of the vascular hypothesis. It is restated here without citation, therefore, in its two basic forms, with the awareness that the separation between them is academic. *presented before the Obstetrical and Gynecological Section of the Baltimore City Medical Society, Feb. 13, 1948. 1037
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1918
The first, a mechanical concept, is based on the observations that the coiled arterioles increase rapidly in complexity and extent as the secretory phase of t,he cycle progresses. This increasing complexity is supposed to reach a point at which it impedes the flow of blood t o the endometrium, producing ischemia,
Fig. l.-Projection reCOnStruCtiOR (X20) of the lumen of 8 coiled arteriole on the twentysixth day of an anovulatory cycle. One ovary contained a large cystic follicle. By this stage the vessel of an anovulatory Cycle is usually more complex than this, as may be seen in Figs. 6 and ‘7. The simplicity of this vessel, as compared with that in Fig. 2, is striking and somewhat overstates the case. Reproduced from Daron, Am. J. Anat. 58: 405, 1936, Fig. 9. Fig. 2.-ProJection reconstruction (X20) of the lumen of a coiled arteriole on the thirtieth day of an ovulatory cycle. Branching occurs at A but only one branch has been reconstructed. Note the complexity of this vessel and compare with Figs. 8 and 0, which illustrates a similar vessel, on the first day of menstruation. The contrast with Fig. 1 requires no comment. Reproduced from Daron, Am. J. Anat. 58: 403, 1936, Fig. 5. Fig. 3.-Schlegel’s sketch of endometrial vasculature of the human uterus as seen in injected material. The coiled arteriole ascends between two large columns of veins. At the asterisk and at two other places arteriovenous anastomoses are indicated. This is a high13 diagrammatic representation. Reproduced from Srhleael. Nonl. Med. 24: 2061. 1947, Fig. 2.
which then sets off the chain reMion of menstruation. The other, a pharmacodynamic concept, st,emsfrom the observation that prolonged periods of vasoconstriction are invariable precursors of the other menstrual changes. The gr’owih and differentiation of the coiled arterioles are presumed to render them srnsi tive to the action of vasomotor substances. These then produce vasoconstriction, ischemia, and menstruation. Both concepts assume that continued growth of a complex wiled aiGriole is a necessary precursor of menstruation. In this sense, the hypothesis of a vascular basis of menstruation as stated by many authors. compounded freelp of ideas from both of the concepts stated
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above, bypasses and even contradicts the earlier work as the common precursor of menstrual flow. As will a conclusion is quite erroneous. A new factor in this vascular explanation has been observations of arteriovenous anastomoses in human
1039 on hormone withdrawal be discussed below, such introduced by the recent endometrium
Fig. 4.-Section of human endometrium (x90). A large venous lake and several glands be seen. At the arrow, an arteriole enters the venous lake. Reproduced from Schlegel, Med. 24: 2067, 1947, Fig. 10. At this magnification. the identifldation of the vessel Fig. 5.-Detail of Fig. 4 (x360). entering the venous lake is by no means as definite as at the lower magnification, although some detail is undoubtedly lost in photography. Reproduced from Schlegel, Nord. Med. 24: 2006. 1947. Fig. 9. may Nord.
Dalgaard4 and Schlegelz3 have independently reported the presence of shunts between the branches of coiled arterioles and venous lakes of the functional zone. As described by Daron, 6 these venous lakes are dilated venules which appear shortly before menstruation in the middle third of the endometrium. Schlegel’s sketch of these vessels is reproduced in Fig. 3. His first observation of anastomoses was made in human uteri injected with colored substances under high pressures. Under the microscope, after sectioning the uteri, Schlegel was able to see points where his red arterial injection mass met the blue venous material without the intervention of a capillary b.ed. Dalgaard, who injected India ink into the arteries, found large numbers of ink particles in the venous lakes. Both authors were later able to find the anastomoses in uninjected histologic preparations. One such anastomosis is shown in Figs. 4 and 5, which are made from Schlegel’s original photographs. Schlegel and Dalgaard agree that these shunts occur with increased frequency in the secretory phase of the menstrual cycle. Schlegel suggests that eventually so much of the arterial blood is shunted into the venous system that a capillary ischemia results. This then precipitates endometrial, breakdown and menstruation. He also argues that the presence of arteriovenous anastomoses provides an ideal vasculature for the establishment of placental circulation.
The existence of these shunts cannot be accepted without reservations. Hartelmez’ hi reported his inability to find anastomoses in the endometrium ol The very high presthe rhesus monkey, but this may be a species difference. sures employed by Schlegel and Dalgaard for injection raise a question about the production of artefact.s. It is certainly difficult to make a positive identificaSerial sections tion of so small a vessel as that seen in Figs. 4 and 5 as arteriolar. of endometrium are required t,o prove the presence of these arteriovenous anastomoses conclusively. Nevert,heless, t,he fact that these structures have been observed independently by two workers makes subsequent confirmation appear Schlege12” has recent,ly reported clinical studies of the effect, of ephedrine likely. on dysmenorrhea, based upon t,hc possible vasomotor action of this drug on the arleriovenous anastomoses.
Wig. C-Outline drawing of a section of endometrium of the rhesus monkey (x25) on the twenty-eighth day of an anovulatory cycle. This and Fig. 8 were made by printing photographs of these sections and then drawing in the outlines of the superAcia1 epithelium, glands and arterioles. The myometrium was sketched in schematically. The photograph was then bleached out. The ai-teriolar fleld is restricted to the inner half of the endometrium and is relatively simple as compared with Fig. 8. Reproduced from Kaiser, Anat. Rec. 99: 215, 1947, Fig. 0, with changes. The vessel walls are compact Fig. 7.-Photograph of the arteriolar field in Fig. b: (x100). and eosinophilic. Reproduced from Kaiser. rlnat. Rec. 99: 221, 1947, Fig. 14.
It is dificnlt. to explain the amenorrhea of’ early pregna.ncy by the current hypothesis of a vascular mechanism for the initiation of menstruation. Although no special study has been devoted to this matter, it appears reasonable to assume that the coiled arterioles o-f the endometrium in the relat,ively vast area removed from the site of implantation different,iate to the same extent as those OS the nonpregnant, uterus, at least in the first. fourteen days after ovulation. The same assumption may be made in reference to arteriovenous anastomoses.
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Number
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Nevertheless, bleeding does not usually occur in the pregnant animal. Schlegel attempts to account for this by postulating a special local effect of chorionic gonadotropin which increases the “irrigation coefficient” of the capillary bed and thus prevents anoxemia. There are still other objections to the vascular explanation. It has been repeatedly observed that the coiled arterioles found in the presence of ovulatory menstruation differ considerably from those seen during anovulatory bleeding.12 Despite this fact, the clinically observed bleeding is identical in the two conditions by all our present criteria. The major differences in the appearance of coiled arterioles of the rhesus monkey in these two circumstances are shown in Pigs. 1, 2, 6, 7, 8, and 9. Figs. 6 and 7 depict the typical appearance of a coiled arteriole on the twenty-eighth day of an anovulatory cycle. They demonstrate maximum anovulatory growth. In contrast, Figs. 8 and 9 show the vessels
Pig. %-Outline drawing of a section of endometrium of the rhesus monkey (x25) on the flrst day of ovulatory menstruation. The arteriolar field is in the middle of the endometrium and branches are seen extending well out toward the superficial epithelium. The Aeld is more complex than in Fig. 6. Reproduced from Kaiser, Anat. Rec. 99: 215, 1947, Fig. 1. Fig. 9.-Photograph of the arteriolar field in Fig. 8 (x100). The arteriolar walls are swollen and much less eosinophilic than these in Fig. 7. Reproduced from Kaiser, Anat. Rec. 99: 217, 1947. Fig. 9.
in the endometrium at the onset of menstruation in an ovulatory cycle. Comparing Figs. 1 and 2, and 4 and 6, it can be seen that the vessel of ovulatory menstruation is larger, more complex, and reaches further out toward the superficial epithelium. Its area of greatest coiling is in the middle third of the endometrium. In Figs. 7 and 9, higher magnification reveals that the vessel walls in ovulatory cycles are thicker and stain less deeply. These differences
1 ( ,lr!
KAISEX
4~1. J. Obst. & Gynet. December. 1948
are known to be an effect of progesterone. I jetailed studies with cytochemical &hniques are required to prove t,heir functional significance. It must be remembered that bleeding can and does occur from an endometrium with a much simpler arteriolar bed than these. Such is the case in bleeding following oophorectomy or spinal cord transection done at the midinterval, for example. -Uthough no study has been made of this subject, coiled arterioles are not conspicuous in t,he presence of endometrial hyperplasia, despite the bleeding with whkh this condition is associated. Finally, there is suggestive evidence that blreding can occur in the rhesus monkey under experimental conditions without, any prolifrrat,ion of coiled arterioles at all ( Kaiser14). Menstruation, al. least in the form of microscopic cyclic blceding in the absence of coiled arterioles, has recently been shown bs Kaiser’” to be the normal condition in the New World monkeys. These animals, which are closely rclatrd ant~hropologicall?- to the other Simiae, including the rhesus monkey and man, were long believed not to menstruate. However, more detailed studies by Goodman and Wislocki,” and Hamlett,” using daily vaginal lavage, have revealed c*yclic ut,erine bleeding of microscopic proportions in the New World species. 7%~ endomet,rium of these platOyrrhinc monkeys goes t,hrough a cycle much like that of the rhesus and the human being (Dempsey’). Despite this, a special study of the vasculature of the platyrrhine endometrium has demonstratetl that. t.here are no coiled arterioles present. Instead, there is a very simple system of small arterioles which run through the endometrium almost without contort&n after branching once or twice in the basalis. These vessels do not. Two of them may be seen at the appear to undergo any cyclic alterations. arrows in Fig. IO. This illustration depicts the appearance of ovulatory menstruation in the endometrium of a capnchin monkey. The contrast between the a.rt,erioles in Figs. 7 and 9 and those in Fig. 10 does not require emphasis. These observations indicate t,hat the current explanation of menstruation I)ased. upon alt,erations of the coiled art,erioles fails to account for much that, is known about t,he menstrual process. Before a vascular explanation can be abandoned, more information is needrd concerning the contraction cones deqeribed by Daron.” He pointed out that the arcuate art,eries of the myometrium traverse the muscle parallel to the serosal surface and give rise to the radial arlerirs which run at right angles to it. These then travel toward the uterine c*avitp and divide into two types of vessels. One type enters the endometrium t(i hecome a basal arteriole. the other to become a coiled arteriole. In several menstruating uteri, Daron observed that t,he radial arteries which led to coiled a.rterioles are constricted so as to form a cone of contraction in the zone of myometrium a,djacent to t,he endometrium. $his may be seen st,rikingly in Fig. 11, from Daron’s original preparation. It is clear that such a constriction would effectively occlude the blood supply of the endometrium. Okkels and Engle’” and Hasner.‘” who have described the mirroscopic structure of the myometrial radial arteries and their branches have unfortunately not discussed this phenomenon. Indeed, Okkels and Engle appear to describe contractile tissue only in the walls of the basal arterioles. If, however, there are structures
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capable of occluding blood supply to the vessels which supply the spongiosa and functionalis, then a simple vascular explanation of menstruation may be possible regardless of the presence or absence of coiled a%erioles. It may be noted here that the sole study of lymphatic channels of the endometrium of the rhesus monkey has indicated that lymphatics are absent from the spongiosa and functionalis. Hence menstruation may be in part due to an inadequate mechanism for the resorption of tissue breakdown products following the cessation of metabolic support. Reynoldszl has recently discussed this matter more detail.
Influence of Past Cycles on Endometrium A most significant contribution to the understanding of abnormalities of menstruation has recently been made by Phelps as a culmination of a series of studies31 I73181I3 in the Department of Obstetrics and Gynecology of Vanderbilt University Medical School. These have followed the observation by Zuckermanz8 that the effect of a single dose of estrogen on the monkey is affected by its response to and distance in time from previous estrogen stimulation. Phelpslg has now directed attention to the fact.or of previous tretament in the production of menstrual disorders in the rhesus monkey. She states that :
1044
R A18EK
.im. J. Obst. & Gyner. December. 1918
by the components, relative any given episode of uterine bleeding is . . . influenced strength and duration of action of hormonal stimuli acting prior to application of the current In other words, the influenw of a single course of stimulation by ovarian hormones stimulus. is not limited to the cycle which that course of stimulation represents. Its influence extends through at least one subsequent cycle and probably through more than one. This influence upon subsequent cycles is mediated at least in pxrt. through the structural changes pro&reed in the endometrial vascular bed. These chauges may be transient or permanent, i.e., carried over into the next cycle. The specific vascular architecture existing at the beginning of any single c!yrle h:w an important influence upon the duration of the uterine bleeding in that cycle.” I
I
.
.
.
It. is evident from t.his t.hat to function r~ormalIg t,he cgithelium! stroma, and l)lood vessels must dcvrlol~ silllult-an~ousl~ to the same level of functional c*almcity. It is not enough that the cl)ithelium alone develops. Hertig’s essay” (III the ctndometrium during t,he human ~yclc unfortunately does not iru*ludc sufficiently correlated reference to IIW arterioles. A correlated study of endometrium and arterioles throughout the c,vc*lc~in the human being would provide a base line with which the endometria of abnormal reproductive cycles could he r*omparecl. It has long been assumed that if the ovary forms a corpus luteum, all the necessary events for successful inlplantat.ion inevitably follow. There is, however, little reason to assume that ever!. corpus lnteum which forms reaches the level of hormone production nccess;~ry for the coordinated growth of all endometrial strueturcs. (%rtainl~- there mlist on occasion be a failure to form a fnnct ioning corpus luteum. 1-nder these circumstances, endometrial growth, and tht< growt,h of coiled arterioles in those species in which they are present, does not proceed to its fullest extent.. This. in turn, as Phelps emphasizes, sets the stage for further endometrial anomalies in later cycles. Brewer and *Jones,” discussing corpus luteum-endometrium relationships. point out that there is considerable variation, especially at. the end of the cycle. They report one case in which an a.pparently normal corpus luteum was associated with endometrium which showed no evidence of past or present secretory activity. They surmise that this reflects either failure of the corpus luteum to function or failure of the endometrium to respond. They also point out that these variations are quite common. The observation of the activity of cndometrial epithelium on one occasion, or the determination of hormone levels in one cycle would, t,herefore, appear lo be only the start of a thorough invest,igation of menstrual abnormalities. Brfore a, therapeutic regime directed al the correction of infertility on the basis c,f menstrual abnormalities ean IW clrc:lared a success, all the elements of the endomet~rium, the rpit,helium, the stroma, and the blood vessels, must have ret.arned to normal. At. present, it can be suggested t,hat certain kinds of incoordinate. growth of these three elements may be related to certain types of functional abnormality. If t,his be the case, endometrial biopsy should prove 1I) be of inrreasing value as an index of therapy.
Discussion Menst,ruation
regression.
is but one phase of a continually It is the period of return to a resting
varying cycle of growth and condition of an endometrium
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which has undergone a period of growth. Once endometrial growth has occurred, a steady supply of metabolites, increased over that required for the resting state, must be maintained if regression is to be prevented. Further, the metabolites must be supplied in ever increasing quantities if continued growth is to occur. The steroid sex hormones provide the growth stimulus to the endometrium and thereby regulate its metabolic needs and participate in its metabolic support. When metabolic support is withdrawn, regression begins. This statement is true foY all mammals.
Fig. ~;~P~lWmulus
12.-Transverse section of a uterine horn of the South African elephant shrew. myurus (X25). This animal has recently ovulated. The mesometrial border is at two layers of myometrium can be readily made out. The glands and stroma are uniform in appearance throughout the circumference of the horn. Reproduced from van der Horst and Gillman, South African J. M. SC. 6: 1941, Fig. 3. Fig. 13.7Transverse section of a uterine horn (x25) of the elephant shrew showing a k;r endometrial polyp. This is the normal state when ovulation is not followed by implantaThe uterine glands beneath it are The polyp always develops on the mesometrial side. dilated, while those elsewhere ‘are small. The stroma away from the polyp is dense and compact, while between the polyp and the dilated glands remnants of stromal edema can be seen. The polyp itself has undergone necrosis, although the covering epithelium is still intact as a very thin layer not visable mat this magnification. It is immediately following this stage that Reproduced from van der Horst and Gillman, South bleeding occurs from the necrotic area. African J. M. SC. B: 1941, Fig. 12. The
Why, then, do only certain primates menstruate! There are two major clues to an answer. Van der Horst and Gilman 25y26 have observed cyclic uterine bleeding in the Sout,h African elephant shrew which is classed by most taxonomists as a rodent. The endometrium of this animal responds to progesterone by forming a large endometrial polyp, almost a deciduoma. This polyp grows until, at the end of the cycle, it undergoes necrosis, hemorrhage, and desquamation. This may be seen in Figs. 12 and 13. It appears that this remarkable growth exceeds the capacity of the uterus for resorption of tissue and tissuebreakdown products. This is in all likelihood also true of the primate endomeThere are no lymphatic channels present to provide ready egress for trium.
1046
RAISER
Am. J. Obst. & Gynec. December. 1948
They remain the eatabolites formed following withdrawal of metabolic support. in situ and cause further tissue destruction until the cndometrium is shed down to t,he area maintained by the capillary bed of basal arterioles. The ot,her major clue is Markee’s observation I5 that regression in the rhesus monkey is not necessarily followed by menstruation provided that it proceeds slowly. By withdrawing estrogens gradually over a long period of time, he was able to produce transition from full growth to a resting state without necrosis, hemorrhage, or desquamation. The factor of time is, therefore, of crucial impo?Zance. The mechanisms for resorption which do exist in the primate endometrium do not operate with sufficient, speed to prevent an accumulation of loxic substances which is lethal to the tissue itself. This aspect of the problem oI’ menstruation has received hut a fraction of the study it deserves. It, is unlikely t.hat t,he coiled arterioles play any significant role in these basic events. Kaiser has described the absenceof such vesselsin the endometrium (JI’ menstruating New World monkeys. Hc has also observed their almost complete absence in the endometrium of rhesus monkeys which have received massive doses of estrogens. Other animals given the same doses manifested uterine bleeding upon withdrawal of the hormone. Finally, it has been repeatedly observed in the macaque that there are no differences in uterine bleeding between ovulatory and anovulatory cycles. The major differences bet,ween the coiled arterioles in these two kinds of cycles have been discussed. This does not refute 3larkee’s conclusion that, when present, these arterioles act to regulate the extent of hemorrhage. h’evertheless, menstrual bleeding occurs whet,her coiled arterioles arc complex, simple, or absent altogether. It setms much more likely that the coiled arteriole is of principal importancr in the process of implantation of the embryo. The evidence for this is as yet only indirect. Ramsey has made a beginnin g in her study of the changes of the endometrial vasculature during pregnancy in the rhesus monkey.*O Phelps Ims produced evidence that menstrual irregularities are associated with anomalous growth of the coiled arterioles in rhesus. This may therefore offer further explanation of the relative sterility of women with menstrual irregularities. Phelps’ other observation, that the effects of hormone administration are delIendent, at least in part on the previous hormonal history of the subject as rcHeeled in t,he state of the coiled arterioles, has very broad implications in t,he study of st,rrilit~y. Some of these have been suggested. The further investigation of the association of the coiled arterioles with the implantation of the fertilized ovum, especially in the light of this anamnestic vascular phenomenon described by Phelys. can be expected to yield results of great experimental nncl clinical interest. The author wishes to thank Dr. Garman II. Daron of the University of Oklahoma and I)r. Jorgen U. Schlegel of the University of Copenhagen for their generosity in lending their original materials for reproduction in this paper. The publishers of NOTdiSk Medicin, the .i?zafomical Record, the American Journal of Anatomy and the So&h African JOUTVUL~ of Medical Sciences generously gave permission for reproduction of figures which originally appeared in their publications.
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References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. i3. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Bartelmez, G. W.: Anat. Rec. 97: 380,1947. Brewer, J. I., and Jones, H. 0.: Ax J. OBST. & GYNEC. 54: 561~575,1947. Cleveland, R.: Endocrinology 28: 388-405, 1941. Dalgaard, J. B.: Acta obst. et gynec. Scandinav. 26: 342-378,1946. Daron, G. H.: Am. J. Anat. 58: 349-419, 1936. Daron, G. H.: Anat. Rec. 67: Suppl. 13,1937. Dempsey, E. W.: Am. J. Anat. 64: 381-405, 1939. Goodman, L., and Wislocki, G. B.: Anat. Rec. 61: 379-387,1935. Hamlet& G. W. D.: Anat. Rec. 73: 171-187, 1939. Hasner, E.: Endometriets vasculaere Cyklus, Copenhagen, 1946. Hertig, A. T.: Diagnosing the Endometrial Biopsy in Diagnosis in Sterility, ed. by E. T. Engle, Springfield, Illinois, 1946, Charles C Thomas. Kaiser, I. H.: Anat. Rec. 99: 199-226, 1947. Kaiser, I. H.: Anat. Rec. 99: 353-368, 1947. Endocrinology (in press). Kaiser, I. H.: Markee, J. E.: Carnegie Contrib. to Embryol. 28: 219-308, 1940. Okkels, Harald, and Engle, E. T.: Acta path. et microbial. Scandinav. 15: 150-168, 1938. Phelps, H.: Endocrinology 39: 105-119, 1946. Phelps, D. H.: Am. J. Anat. 79: 167-198, 1946. Phelps, D: H.: J. Clin. Endocrinol. 7: 611-623, 1947. Ramsey, E. M.: Carnegie Contrib. to Embryol. (To be published.) Reynolds, S. R. M.: J. A. M. A. 135: 552-557, 1947.. Saito, 0.: Beitrjige zum Studium der Uterus-gefisse, Okayama-Igakki-Zasshi, 470-471, 1926. Schlegel, J. U.: Acta anat. 1: 284-325, 1945. Schlegel, J. U.: Nord. Med. 34: 1153-1159, 1947. van der Horst, C. J., and Gillman, J.: South African J. M. SC. 6: 27-47, 1941. van der Horst, C. J., and Gillman, J.: South African J. M. SC. 7: 134-143, 1942. Wislocki, G. B., and Dempsey, E. W.: Anat. Rec. 75: 341-363, 1939. Zuckerman, 5.: J. Endocrinol 2: 438-443, 1941.
CONCEPTS
OF MENSTRUATION”
IRWIN H. KAISER; M.D., BALTIMORE, M.D. (From
the Department Department
of
Embryology, Obstetrics,
of
Carnegie Institution of Washington. Sinai Hospital of Raltimore)
and
the
LEEDING is the most striking feature of the menstrual process. A large part of the clinical and laboratory study of menstruation in the past two decades has, therefore, b,een directed toward the blood vessels of the endometrium. On the basis of this work, an explanation of cyclic uterine bleeding as a consequence of alterations of the coiled arterioles of the endometrium has gained widespread acceptance. Unfortunately, this explanation has been carried so far that it now fits only certain special cases. The most recent laborat,ory findings as well as many familiar clinical observations require a return to a more general physiologic concept of menstruation as a result of withdrawal of metabolic support of the endometrium.
B
It has been known for some time that the vasculature of the endometrium undergoes cyclic changes along with the glands and stroma (Saito,22 DarorP). The basal arterioles, situated in the deepest portion of the endometrium, are not shed in the menstrual, discharge and do not participate in these cyclic changes. The coiled arterioles, which eventually reach almost to the superficial epithelium, Just after the completion of bleeding, the manifest remarkable alterations. endometrium is shallow and the coiled arterioles have but a few loops. As the follicular phase proceeds, the endometrium thickens and the arterioles add loops and lengthen, remaining confined to the inner half of the mucous membrane. If ovulation fails to occur and growth continues, due to continued estrogen stimulation, vessels such as those in Figs. 1, 6, and 7 develop. If, however, a functioning corpus luteum is formed, the coiled arterioles become much more complex and extend further out into the endometrium as the secretory changes of the glands and stroma take place. With the approach of menstruation, the contortion and buckling of the vessels become extreme, as in Figs. 2, 8, and 9. The distal portion of the vessel is lost thereafter in the menstrual discharge. Markeel has added greatly to the understanding of these changes by describing them as they take place in endometrium transplanted to the anterior chamber of a rhesus monkey’s eye. He observed that the bulk of endometrial bleeding is arteriolar in origin and that, therefore, the coiled arterioles control the amount and rate of menstrual hemorrhage. The explanation of menstruation as a consequence of vascular changes is based primarily on these observations In the years that have followed the publication of these findings, so many interpretations of their meaning, all of them similar, have been made in textbook and monograph discussions of menstruation that it would be unfair to cite any one author’s exposition of the vascular hypothesis. It is restated here without citation, therefore, in its two basic forms, with the awareness that the separation between them is academic. *presented before the Obstetrical and Gynecological Section of the Baltimore City Medical Society, Feb. 13, 1948. 1037
10%
KATREH
Am. .I. Obst. & Gynec. December,
1918
The first, a mechanical concept, is based on the observations that the coiled arterioles increase rapidly in complexity and extent as the secretory phase of t,he cycle progresses. This increasing complexity is supposed to reach a point at which it impedes the flow of blood t o the endometrium, producing ischemia,
Fig. l.-Projection reCOnStruCtiOR (X20) of the lumen of 8 coiled arteriole on the twentysixth day of an anovulatory cycle. One ovary contained a large cystic follicle. By this stage the vessel of an anovulatory Cycle is usually more complex than this, as may be seen in Figs. 6 and ‘7. The simplicity of this vessel, as compared with that in Fig. 2, is striking and somewhat overstates the case. Reproduced from Daron, Am. J. Anat. 58: 405, 1936, Fig. 9. Fig. 2.-ProJection reconstruction (X20) of the lumen of a coiled arteriole on the thirtieth day of an ovulatory cycle. Branching occurs at A but only one branch has been reconstructed. Note the complexity of this vessel and compare with Figs. 8 and 0, which illustrates a similar vessel, on the first day of menstruation. The contrast with Fig. 1 requires no comment. Reproduced from Daron, Am. J. Anat. 58: 403, 1936, Fig. 5. Fig. 3.-Schlegel’s sketch of endometrial vasculature of the human uterus as seen in injected material. The coiled arteriole ascends between two large columns of veins. At the asterisk and at two other places arteriovenous anastomoses are indicated. This is a high13 diagrammatic representation. Reproduced from Srhleael. Nonl. Med. 24: 2061. 1947, Fig. 2.
which then sets off the chain reMion of menstruation. The other, a pharmacodynamic concept, st,emsfrom the observation that prolonged periods of vasoconstriction are invariable precursors of the other menstrual changes. The gr’owih and differentiation of the coiled arterioles are presumed to render them srnsi tive to the action of vasomotor substances. These then produce vasoconstriction, ischemia, and menstruation. Both concepts assume that continued growth of a complex wiled aiGriole is a necessary precursor of menstruation. In this sense, the hypothesis of a vascular basis of menstruation as stated by many authors. compounded freelp of ideas from both of the concepts stated
Volume Number
56 6
NEWER
CONCEPTS
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above, bypasses and even contradicts the earlier work as the common precursor of menstrual flow. As will a conclusion is quite erroneous. A new factor in this vascular explanation has been observations of arteriovenous anastomoses in human
1039 on hormone withdrawal be discussed below, such introduced by the recent endometrium
Fig. 4.-Section of human endometrium (x90). A large venous lake and several glands be seen. At the arrow, an arteriole enters the venous lake. Reproduced from Schlegel, Med. 24: 2067, 1947, Fig. 10. At this magnification. the identifldation of the vessel Fig. 5.-Detail of Fig. 4 (x360). entering the venous lake is by no means as definite as at the lower magnification, although some detail is undoubtedly lost in photography. Reproduced from Schlegel, Nord. Med. 24: 2006. 1947. Fig. 9. may Nord.
Dalgaard4 and Schlegelz3 have independently reported the presence of shunts between the branches of coiled arterioles and venous lakes of the functional zone. As described by Daron, 6 these venous lakes are dilated venules which appear shortly before menstruation in the middle third of the endometrium. Schlegel’s sketch of these vessels is reproduced in Fig. 3. His first observation of anastomoses was made in human uteri injected with colored substances under high pressures. Under the microscope, after sectioning the uteri, Schlegel was able to see points where his red arterial injection mass met the blue venous material without the intervention of a capillary b.ed. Dalgaard, who injected India ink into the arteries, found large numbers of ink particles in the venous lakes. Both authors were later able to find the anastomoses in uninjected histologic preparations. One such anastomosis is shown in Figs. 4 and 5, which are made from Schlegel’s original photographs. Schlegel and Dalgaard agree that these shunts occur with increased frequency in the secretory phase of the menstrual cycle. Schlegel suggests that eventually so much of the arterial blood is shunted into the venous system that a capillary ischemia results. This then precipitates endometrial, breakdown and menstruation. He also argues that the presence of arteriovenous anastomoses provides an ideal vasculature for the establishment of placental circulation.
The existence of these shunts cannot be accepted without reservations. Hartelmez’ hi reported his inability to find anastomoses in the endometrium ol The very high presthe rhesus monkey, but this may be a species difference. sures employed by Schlegel and Dalgaard for injection raise a question about the production of artefact.s. It is certainly difficult to make a positive identificaSerial sections tion of so small a vessel as that seen in Figs. 4 and 5 as arteriolar. of endometrium are required t,o prove the presence of these arteriovenous anastomoses conclusively. Nevert,heless, t,he fact that these structures have been observed independently by two workers makes subsequent confirmation appear Schlege12” has recent,ly reported clinical studies of the effect, of ephedrine likely. on dysmenorrhea, based upon t,hc possible vasomotor action of this drug on the arleriovenous anastomoses.
Wig. C-Outline drawing of a section of endometrium of the rhesus monkey (x25) on the twenty-eighth day of an anovulatory cycle. This and Fig. 8 were made by printing photographs of these sections and then drawing in the outlines of the superAcia1 epithelium, glands and arterioles. The myometrium was sketched in schematically. The photograph was then bleached out. The ai-teriolar fleld is restricted to the inner half of the endometrium and is relatively simple as compared with Fig. 8. Reproduced from Kaiser, Anat. Rec. 99: 215, 1947, Fig. 0, with changes. The vessel walls are compact Fig. 7.-Photograph of the arteriolar field in Fig. b: (x100). and eosinophilic. Reproduced from Kaiser. rlnat. Rec. 99: 221, 1947, Fig. 14.
It is dificnlt. to explain the amenorrhea of’ early pregna.ncy by the current hypothesis of a vascular mechanism for the initiation of menstruation. Although no special study has been devoted to this matter, it appears reasonable to assume that the coiled arterioles o-f the endometrium in the relat,ively vast area removed from the site of implantation different,iate to the same extent as those OS the nonpregnant, uterus, at least in the first. fourteen days after ovulation. The same assumption may be made in reference to arteriovenous anastomoses.
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Nevertheless, bleeding does not usually occur in the pregnant animal. Schlegel attempts to account for this by postulating a special local effect of chorionic gonadotropin which increases the “irrigation coefficient” of the capillary bed and thus prevents anoxemia. There are still other objections to the vascular explanation. It has been repeatedly observed that the coiled arterioles found in the presence of ovulatory menstruation differ considerably from those seen during anovulatory bleeding.12 Despite this fact, the clinically observed bleeding is identical in the two conditions by all our present criteria. The major differences in the appearance of coiled arterioles of the rhesus monkey in these two circumstances are shown in Pigs. 1, 2, 6, 7, 8, and 9. Figs. 6 and 7 depict the typical appearance of a coiled arteriole on the twenty-eighth day of an anovulatory cycle. They demonstrate maximum anovulatory growth. In contrast, Figs. 8 and 9 show the vessels
Pig. %-Outline drawing of a section of endometrium of the rhesus monkey (x25) on the flrst day of ovulatory menstruation. The arteriolar field is in the middle of the endometrium and branches are seen extending well out toward the superficial epithelium. The Aeld is more complex than in Fig. 6. Reproduced from Kaiser, Anat. Rec. 99: 215, 1947, Fig. 1. Fig. 9.-Photograph of the arteriolar field in Fig. 8 (x100). The arteriolar walls are swollen and much less eosinophilic than these in Fig. 7. Reproduced from Kaiser, Anat. Rec. 99: 217, 1947. Fig. 9.
in the endometrium at the onset of menstruation in an ovulatory cycle. Comparing Figs. 1 and 2, and 4 and 6, it can be seen that the vessel of ovulatory menstruation is larger, more complex, and reaches further out toward the superficial epithelium. Its area of greatest coiling is in the middle third of the endometrium. In Figs. 7 and 9, higher magnification reveals that the vessel walls in ovulatory cycles are thicker and stain less deeply. These differences
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are known to be an effect of progesterone. I jetailed studies with cytochemical &hniques are required to prove t,heir functional significance. It must be remembered that bleeding can and does occur from an endometrium with a much simpler arteriolar bed than these. Such is the case in bleeding following oophorectomy or spinal cord transection done at the midinterval, for example. -Uthough no study has been made of this subject, coiled arterioles are not conspicuous in t,he presence of endometrial hyperplasia, despite the bleeding with whkh this condition is associated. Finally, there is suggestive evidence that blreding can occur in the rhesus monkey under experimental conditions without, any prolifrrat,ion of coiled arterioles at all ( Kaiser14). Menstruation, al. least in the form of microscopic cyclic blceding in the absence of coiled arterioles, has recently been shown bs Kaiser’” to be the normal condition in the New World monkeys. These animals, which are closely rclatrd ant~hropologicall?- to the other Simiae, including the rhesus monkey and man, were long believed not to menstruate. However, more detailed studies by Goodman and Wislocki,” and Hamlett,” using daily vaginal lavage, have revealed c*yclic ut,erine bleeding of microscopic proportions in the New World species. 7%~ endomet,rium of these platOyrrhinc monkeys goes t,hrough a cycle much like that of the rhesus and the human being (Dempsey’). Despite this, a special study of the vasculature of the platyrrhine endometrium has demonstratetl that. t.here are no coiled arterioles present. Instead, there is a very simple system of small arterioles which run through the endometrium almost without contort&n after branching once or twice in the basalis. These vessels do not. Two of them may be seen at the appear to undergo any cyclic alterations. arrows in Fig. IO. This illustration depicts the appearance of ovulatory menstruation in the endometrium of a capnchin monkey. The contrast between the a.rt,erioles in Figs. 7 and 9 and those in Fig. 10 does not require emphasis. These observations indicate t,hat the current explanation of menstruation I)ased. upon alt,erations of the coiled art,erioles fails to account for much that, is known about t,he menstrual process. Before a vascular explanation can be abandoned, more information is needrd concerning the contraction cones deqeribed by Daron.” He pointed out that the arcuate art,eries of the myometrium traverse the muscle parallel to the serosal surface and give rise to the radial arlerirs which run at right angles to it. These then travel toward the uterine c*avitp and divide into two types of vessels. One type enters the endometrium t(i hecome a basal arteriole. the other to become a coiled arteriole. In several menstruating uteri, Daron observed that t,he radial arteries which led to coiled a.rterioles are constricted so as to form a cone of contraction in the zone of myometrium a,djacent to t,he endometrium. $his may be seen st,rikingly in Fig. 11, from Daron’s original preparation. It is clear that such a constriction would effectively occlude the blood supply of the endometrium. Okkels and Engle’” and Hasner.‘” who have described the mirroscopic structure of the myometrial radial arteries and their branches have unfortunately not discussed this phenomenon. Indeed, Okkels and Engle appear to describe contractile tissue only in the walls of the basal arterioles. If, however, there are structures
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capable of occluding blood supply to the vessels which supply the spongiosa and functionalis, then a simple vascular explanation of menstruation may be possible regardless of the presence or absence of coiled a%erioles. It may be noted here that the sole study of lymphatic channels of the endometrium of the rhesus monkey has indicated that lymphatics are absent from the spongiosa and functionalis. Hence menstruation may be in part due to an inadequate mechanism for the resorption of tissue breakdown products following the cessation of metabolic support. Reynoldszl has recently discussed this matter more detail.
Influence of Past Cycles on Endometrium A most significant contribution to the understanding of abnormalities of menstruation has recently been made by Phelps as a culmination of a series of studies31 I73181I3 in the Department of Obstetrics and Gynecology of Vanderbilt University Medical School. These have followed the observation by Zuckermanz8 that the effect of a single dose of estrogen on the monkey is affected by its response to and distance in time from previous estrogen stimulation. Phelpslg has now directed attention to the fact.or of previous tretament in the production of menstrual disorders in the rhesus monkey. She states that :
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by the components, relative any given episode of uterine bleeding is . . . influenced strength and duration of action of hormonal stimuli acting prior to application of the current In other words, the influenw of a single course of stimulation by ovarian hormones stimulus. is not limited to the cycle which that course of stimulation represents. Its influence extends through at least one subsequent cycle and probably through more than one. This influence upon subsequent cycles is mediated at least in pxrt. through the structural changes pro&reed in the endometrial vascular bed. These chauges may be transient or permanent, i.e., carried over into the next cycle. The specific vascular architecture existing at the beginning of any single c!yrle h:w an important influence upon the duration of the uterine bleeding in that cycle.” I
I
.
.
.
It. is evident from t.his t.hat to function r~ormalIg t,he cgithelium! stroma, and l)lood vessels must dcvrlol~ silllult-an~ousl~ to the same level of functional c*almcity. It is not enough that the cl)ithelium alone develops. Hertig’s essay” (III the ctndometrium during t,he human ~yclc unfortunately does not iru*ludc sufficiently correlated reference to IIW arterioles. A correlated study of endometrium and arterioles throughout the c,vc*lc~in the human being would provide a base line with which the endometria of abnormal reproductive cycles could he r*omparecl. It has long been assumed that if the ovary forms a corpus luteum, all the necessary events for successful inlplantat.ion inevitably follow. There is, however, little reason to assume that ever!. corpus lnteum which forms reaches the level of hormone production nccess;~ry for the coordinated growth of all endometrial strueturcs. (%rtainl~- there mlist on occasion be a failure to form a fnnct ioning corpus luteum. 1-nder these circumstances, endometrial growth, and tht< growt,h of coiled arterioles in those species in which they are present, does not proceed to its fullest extent.. This. in turn, as Phelps emphasizes, sets the stage for further endometrial anomalies in later cycles. Brewer and *Jones,” discussing corpus luteum-endometrium relationships. point out that there is considerable variation, especially at. the end of the cycle. They report one case in which an a.pparently normal corpus luteum was associated with endometrium which showed no evidence of past or present secretory activity. They surmise that this reflects either failure of the corpus luteum to function or failure of the endometrium to respond. They also point out that these variations are quite common. The observation of the activity of cndometrial epithelium on one occasion, or the determination of hormone levels in one cycle would, t,herefore, appear lo be only the start of a thorough invest,igation of menstrual abnormalities. Brfore a, therapeutic regime directed al the correction of infertility on the basis c,f menstrual abnormalities ean IW clrc:lared a success, all the elements of the endomet~rium, the rpit,helium, the stroma, and the blood vessels, must have ret.arned to normal. At. present, it can be suggested t,hat certain kinds of incoordinate. growth of these three elements may be related to certain types of functional abnormality. If t,his be the case, endometrial biopsy should prove 1I) be of inrreasing value as an index of therapy.
Discussion Menst,ruation
regression.
is but one phase of a continually It is the period of return to a resting
varying cycle of growth and condition of an endometrium
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which has undergone a period of growth. Once endometrial growth has occurred, a steady supply of metabolites, increased over that required for the resting state, must be maintained if regression is to be prevented. Further, the metabolites must be supplied in ever increasing quantities if continued growth is to occur. The steroid sex hormones provide the growth stimulus to the endometrium and thereby regulate its metabolic needs and participate in its metabolic support. When metabolic support is withdrawn, regression begins. This statement is true foY all mammals.
Fig. ~;~P~lWmulus
12.-Transverse section of a uterine horn of the South African elephant shrew. myurus (X25). This animal has recently ovulated. The mesometrial border is at two layers of myometrium can be readily made out. The glands and stroma are uniform in appearance throughout the circumference of the horn. Reproduced from van der Horst and Gillman, South African J. M. SC. 6: 1941, Fig. 3. Fig. 13.7Transverse section of a uterine horn (x25) of the elephant shrew showing a k;r endometrial polyp. This is the normal state when ovulation is not followed by implantaThe uterine glands beneath it are The polyp always develops on the mesometrial side. dilated, while those elsewhere ‘are small. The stroma away from the polyp is dense and compact, while between the polyp and the dilated glands remnants of stromal edema can be seen. The polyp itself has undergone necrosis, although the covering epithelium is still intact as a very thin layer not visable mat this magnification. It is immediately following this stage that Reproduced from van der Horst and Gillman, South bleeding occurs from the necrotic area. African J. M. SC. B: 1941, Fig. 12. The
Why, then, do only certain primates menstruate! There are two major clues to an answer. Van der Horst and Gilman 25y26 have observed cyclic uterine bleeding in the Sout,h African elephant shrew which is classed by most taxonomists as a rodent. The endometrium of this animal responds to progesterone by forming a large endometrial polyp, almost a deciduoma. This polyp grows until, at the end of the cycle, it undergoes necrosis, hemorrhage, and desquamation. This may be seen in Figs. 12 and 13. It appears that this remarkable growth exceeds the capacity of the uterus for resorption of tissue and tissuebreakdown products. This is in all likelihood also true of the primate endomeThere are no lymphatic channels present to provide ready egress for trium.
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They remain the eatabolites formed following withdrawal of metabolic support. in situ and cause further tissue destruction until the cndometrium is shed down to t,he area maintained by the capillary bed of basal arterioles. The ot,her major clue is Markee’s observation I5 that regression in the rhesus monkey is not necessarily followed by menstruation provided that it proceeds slowly. By withdrawing estrogens gradually over a long period of time, he was able to produce transition from full growth to a resting state without necrosis, hemorrhage, or desquamation. The factor of time is, therefore, of crucial impo?Zance. The mechanisms for resorption which do exist in the primate endometrium do not operate with sufficient, speed to prevent an accumulation of loxic substances which is lethal to the tissue itself. This aspect of the problem oI’ menstruation has received hut a fraction of the study it deserves. It, is unlikely t.hat t,he coiled arterioles play any significant role in these basic events. Kaiser has described the absenceof such vesselsin the endometrium (JI’ menstruating New World monkeys. Hc has also observed their almost complete absence in the endometrium of rhesus monkeys which have received massive doses of estrogens. Other animals given the same doses manifested uterine bleeding upon withdrawal of the hormone. Finally, it has been repeatedly observed in the macaque that there are no differences in uterine bleeding between ovulatory and anovulatory cycles. The major differences bet,ween the coiled arterioles in these two kinds of cycles have been discussed. This does not refute 3larkee’s conclusion that, when present, these arterioles act to regulate the extent of hemorrhage. h’evertheless, menstrual bleeding occurs whet,her coiled arterioles arc complex, simple, or absent altogether. It setms much more likely that the coiled arteriole is of principal importancr in the process of implantation of the embryo. The evidence for this is as yet only indirect. Ramsey has made a beginnin g in her study of the changes of the endometrial vasculature during pregnancy in the rhesus monkey.*O Phelps Ims produced evidence that menstrual irregularities are associated with anomalous growth of the coiled arterioles in rhesus. This may therefore offer further explanation of the relative sterility of women with menstrual irregularities. Phelps’ other observation, that the effects of hormone administration are delIendent, at least in part on the previous hormonal history of the subject as rcHeeled in t,he state of the coiled arterioles, has very broad implications in t,he study of st,rrilit~y. Some of these have been suggested. The further investigation of the association of the coiled arterioles with the implantation of the fertilized ovum, especially in the light of this anamnestic vascular phenomenon described by Phelys. can be expected to yield results of great experimental nncl clinical interest. The author wishes to thank Dr. Garman II. Daron of the University of Oklahoma and I)r. Jorgen U. Schlegel of the University of Copenhagen for their generosity in lending their original materials for reproduction in this paper. The publishers of NOTdiSk Medicin, the .i?zafomical Record, the American Journal of Anatomy and the So&h African JOUTVUL~ of Medical Sciences generously gave permission for reproduction of figures which originally appeared in their publications.
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References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. i3. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Bartelmez, G. W.: Anat. Rec. 97: 380,1947. Brewer, J. I., and Jones, H. 0.: Ax J. OBST. & GYNEC. 54: 561~575,1947. Cleveland, R.: Endocrinology 28: 388-405, 1941. Dalgaard, J. B.: Acta obst. et gynec. Scandinav. 26: 342-378,1946. Daron, G. H.: Am. J. Anat. 58: 349-419, 1936. Daron, G. H.: Anat. Rec. 67: Suppl. 13,1937. Dempsey, E. W.: Am. J. Anat. 64: 381-405, 1939. Goodman, L., and Wislocki, G. B.: Anat. Rec. 61: 379-387,1935. Hamlet& G. W. D.: Anat. Rec. 73: 171-187, 1939. Hasner, E.: Endometriets vasculaere Cyklus, Copenhagen, 1946. Hertig, A. T.: Diagnosing the Endometrial Biopsy in Diagnosis in Sterility, ed. by E. T. Engle, Springfield, Illinois, 1946, Charles C Thomas. Kaiser, I. H.: Anat. Rec. 99: 199-226, 1947. Kaiser, I. H.: Anat. Rec. 99: 353-368, 1947. Endocrinology (in press). Kaiser, I. H.: Markee, J. E.: Carnegie Contrib. to Embryol. 28: 219-308, 1940. Okkels, Harald, and Engle, E. T.: Acta path. et microbial. Scandinav. 15: 150-168, 1938. Phelps, H.: Endocrinology 39: 105-119, 1946. Phelps, D. H.: Am. J. Anat. 79: 167-198, 1946. Phelps, D: H.: J. Clin. Endocrinol. 7: 611-623, 1947. Ramsey, E. M.: Carnegie Contrib. to Embryol. (To be published.) Reynolds, S. R. M.: J. A. M. A. 135: 552-557, 1947.. Saito, 0.: Beitrjige zum Studium der Uterus-gefisse, Okayama-Igakki-Zasshi, 470-471, 1926. Schlegel, J. U.: Acta anat. 1: 284-325, 1945. Schlegel, J. U.: Nord. Med. 34: 1153-1159, 1947. van der Horst, C. J., and Gillman, J.: South African J. M. SC. 6: 27-47, 1941. van der Horst, C. J., and Gillman, J.: South African J. M. SC. 7: 134-143, 1942. Wislocki, G. B., and Dempsey, E. W.: Anat. Rec. 75: 341-363, 1939. Zuckerman, 5.: J. Endocrinol 2: 438-443, 1941.