Book - Sex and internal secretions (1961) 14
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Section D Biology of Sperm and Ova, Fertilization, Implantation, the Placenta, and Pregnancy
K. STAGES OF DEVELOPMENT AND
LOCATION OF EGGS
The zygotes of the eutherian mammals are remarkably similar in their appearance and rate of development through the various stages of cleavage and formation of the blastocyst. Cleavage consists of a succession of mitotic divisions of the zygote at specific time intervals after karyogamy. The partitioning of the zygote occurs with little or no increase in the total amount of cytoplasm. Salient features of the mechanism of cleavage in different vertebrate types have been reviewed bv Bovd and Hamilton (1952).
Data on the rate of cleavage and transport of fertilized ova through the oviduct in different animals have accumulated much more slowly than one would expect from the availability of material. The most complete information has been obtained for some of the ungulates and laboratory rodents and is presented in tabular form (Table 14.5) from the summary of Hamilton and Laing (1946). The rate of cleavage is an inherent property of the zygote. Thus the cleavage rates of different species of amblystoma reared at the same temperature are significantly different. Similarly, in the rabbit the cleavage rate is consistently more rapid in strains of larger-sized animals than in the smaller-sized races (Castle and Gregory, 1929; Gregory and Castle, 1931). It is interesting that, although the zygotes of the larger-sized race divided more rapidly and contained more cells, embryonic differentiation occurred at the same rate in both races.
Altering the environment of zygotes may also effect the rate of cleavage. Thus the early fertilized eggs of the rat, mouse, hamster, and guinea jiig cleave only irregularly if at all under tissue-culture conditions. If various thio-amino acids are added to the medium in which rabbit zygotes are being cultured, cell division will proceed normally and may even be accelerated (Pincus, 1937; Pincus and Werthessen, 1938; Miller and Reimann, 1940).
846
SPERM, OVA, AND PREGNANCY
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BIOLOGY OF EGGS AND IMPLANTATION
847
Again cleavage may be either partially or completely inhibited by the addition of colchicine to a culture medium containing the fertilized eggs of frogs (Samartino and Rugh, 1946) or rabbits (Pincus and Waddington, 1939). A similar effect is observed when this drug is injected into mated mice (Waldo and Wimsatt, 1945). The rate of cleavage also depends on the amount of stored yolk. This is particularly true in the macrolecithal eggs of frogs and birds.
The peculiar phenomenon of deutoplasmolysis, or extrusion of yolk from fertilized and cleaving eggs, has been described in the bat (Van der Stricht, 1909) , various marsupials (Hartman, 1928), the horse (Hamilton and Day, 1945), the guinea pig (Lams, 1913), the cat (Hill and Tribe, 1924), the pig (Heuser and Streeter, 1929), and the ferret (Hamilton, 1934). In the cleaving eggs of the horse, a large amount of the yolk is extruded into the perivitelline space. The significance of this process is unknown, but it has been suggested that elimination of yolk may be necessary in order to establish a normal nucleocytoplasmic ratio (Levi, 1915).
Except for the monotremes, all mammals have meiolecithal eggs which undergo a complete or holoblastic type of cleavage. A discrepancy in the size of the first two blastomeres has been reported for a number of mammals and seems to be the usual condition (see Amoroso, Griffiths and Hamilton, 1942, for review of this subject).
The second cleavage division occurs in two planes at right angles to each other. Division of the two blastomeres is not necessarily synchronous and accounts for the frequent observation of a 3-cell stage. In an ovum containing two blastomeres of unequal size, the larger cell apparently has some priority in the next two divisions and this probably explains the origin of eggs containing an unequal number of cells. In the 4-cell stage, the blastomeres are arranged in the form of a tetrahedron, due to the preceding orientation of the two mitotic spindles at right angles to each other. Differences in the size of the blastomeres have been recorded in almost every species.
By the end of the 16-cell stage, several of the blastomeres have been moved cen
trally thus forming the morula. In subsequent cleavages, the smaller, peripheral
cells divide more rapidly and an asynchrony, already present, is accentuated.
Then fluids begin to accumulate between
peripheral and central cells, giving rise to
the cavity of the blastocyst.
During cleavage there is a significant diminution in the volume of the total ooplasm. In the first cleavage division of the monkey {Macacus rhesus), Lewis and Hartman (1933) recorded a shrinkage of 44 per cent. During the 1-cell stage of the mouse, Lewis and Wright (1935) noted shrinkage of as much as 25 per cent with a further decrease in volume as cleavage continued. The hamster egg is even more remarkable for the very large volume of its perivitelline space (Austin, 1957).
As mammalian ova of various species are studied, attention is being directed to the dift'erences in the size of blastomeres and rate of cleavage in the hope of finding evidence for the sorting and localization of specific determining substances in the zygote. It has been suggested that in the eggs of the monkey (Lewis and Hartman, 1941), pig (Heuser and Streeter, 1929), goat (Amoroso, Griffiths and Hamilton, 1942) , rabbit (Van Beneden, 1875), and mouse (Sobotta, 1924), the more rapidly dividing blastomeres are the precursors of the trophoblast and the more slowly cleaving cells the precursors of the inner cell mass or the embryo proper.
Even though discrepancies in the size of the first two blastomeres have been described in many mammals, there is at yet little evidence of a qualitative difference between them. Heuser and Streeter (1929) could not find a demonstrable cytologic difference between the first two blastomeres of the pig. Hamilton (1934) suggested that, at least in the ferret, size differences of the blastomeres can be explained by the chance division of the cytoplasm in the first cleavage. Despite the difference in size of the first two blastomeres in the mouse, Gresson
(1941) has shown that the mitochondria are equally divided between them. Furthermore, the observations of Nicholas and Hall
(1942) do not support the theory of absolute determination of the early blastomeres.
848
SPERM, OVA, AND PREGNANCY
These investigators obtained normal young after separating the first two blastomeres of a rat embryo and transplanting them into pregnant host females. From the results of these experiments, they concluded that "the rat egg possesses the capacity to satisfy two of the criteria for equipotentiality: (1) each of the first two parts of the egg may form a whole embryo which develops further than the cleavage stages, and (2) the fusion of two eggs produces one single individual of large size." More recently, Tarkowski (1959) destroyed a single blastomere in 2- and 4-celled mouse eggs by piercing them with a micropipette directly through the zona pellucida. The eggs were then transferred to properly timed recipients. Of 175 half-blastomeres transplanted, 30 per cent had implanted and appeared to be normal except that they were significantly smaller than the controls. Three females gave birth to a total of 6 young which had developed from the experimental eggs. All of the animals were fertile and subsequently gave birth to several litters. Much more experimental work is needed in this area, and perhaps the techniques of transplanting individual blastomeres to the anterior chamber of the eye may open possibilities for further investigations (Fawcett, Wislocki and Waldo, 1947; Runner, 1947).
L. THE AGE OF THE EGG AT THE TIME OF FERTILIZATION
In 1913, Jacques Loeb in his book "Artificial Parthenogenesis and Fertilization" wrote as follows: "The unfertilized mature egg dies in a comparatively short time, which may vary from a few hours to a few weeks according to the species or the conditions under which the egg lives. The death of the unfertilized egg is possibly the only clear case of natural death of a cell, i.e., of death which is not caused by external injuries, and the act of fertilization is thus far the only known means by which the natural death of a cell can be prevented." As studies on the physiology of mammalian gametes are pursued, it is evident that these cells must indeed be listed among those having the shortest life span in the body.
The reproductive processes in most mammals are so timed that spermatozoa reach
the site of fertilization and are ready to penetrate the eggs almost immediately after their extrusion from the follicles.
Developmental defects which result from the over-ripening of gametes before fertilization have been studied in greatest detail in invertebrates and lower vertebrates (Gemmill, 1900; Bataillon, 1901; Grave and Oliphant, 1930). Because of their ready availability, the eggs of the fish and amphibia have been found particularly useful in experimental investigations of this type (Mrsic, 1923, 1930; Witschi, 1952).
Witschi descril)ed a method whereby frogs were induced to retain their mature eggs within the uteri for varying intervals by separating the females from the males and keeping them in dry containers at room temperature. By subsequent removal of the eggs, by either laparotomy or strijiping, the aging gametes could be fertilized by artificial insemination and their development followed. He found that fertilization and development remained relatively normal in eggs which had been retained for 3 to 4 days. However, the sex-determining mechanism was affected in that almost 90 per cent males were produced. Similar alterations in the sex ratio have been reported by Mrsic in the aging eggs of the rainbow trout. If the frog eggs were retained for more than 4 days without fertilization, they gradually became over-ripe and either failed to be fertilized or, if penetrated by a spermatozoon, developed abnormally. After approximately 1 week, all of the eggs retained in the genital ducts became unfertilizable. In amphibia, as in other species, the aging eggs gradually lose their vitality. Witschi's observations are particularly significant in that he followed the development of the over-ripe eggs beyond the stage of metamorphosis and described a number of teratogenic effects of widely divergent nature. Some of the developmental abnormalities encountered were polymyelia, Polydactyly, axial duplications (especially in the region of the head), anencephaly, microcephaly, and failure of normal differentiation of various tissues and organs.
In evaluating the bases for the widely divergent nature of these abnormalities, Witschi suggested that they are expressions of an
BIOLOGY OF EGGS AND IMPLANTATION
849
TABLE 14.6 The fertilizable life of the mammalian ovum
Anim.il
Length of Fertilizable Life
Investigator
Morphologic signs of degeneration appear
within 24 hours after ovulation.
Hartman (1924a)
Mouse
(a) 12 hours. Matings 13 hours after ovulation results in reduced fertility
(b) 6 hours, estimation
(c) 8 hours, experimental
Long (1912)
Lewis and Wright (1935) Runner and Palm (1953)
Hamster
5 hours, experimental
Chang and Fernandez-Cano (1958)
Rat
>12 hours, experimental
Blandau and Jordan (1941)
Guinea pig
>20 hours, experimental
Blandau and Young (1939); Row
lands (1957)
Ferret
>30 hours, experimental
Hammond and Walton (1934)
Rabbit
6 hours, experimental
8 hours, experimental
Hammond (1934)
Chang (1953)
Braden (1952)
Sheep
24 hours, estimation
Green and Winters (1935)
Cow
18-20 hours, experimental
Barrett (1948)
Mare
Short
Day (1940)
Monkey
23 hours, estimation
Lewis and Hartman (1941)
Man
6-24 hours, estimation
Hartman (1936)
interference with either the normal processes of producing or liberating evocators, or the capacity of the embryonic tissues to respond to induction. Of special interest is the finding that the older fertilized eggs frequently gave rise to teratomatous proliferations in the endoderm. When these tumor-like masses were transplanted to older larvae they grew rajjidly and metastasized. Needham (1950) proposed that, because the primary evocator, the principal sex-hormone, and various carcinogens belong to the steroid compounds, the effect of over-ripeness may be related to a disturbance of embryonic sterol metabolism.
The fertilizable life of the mammalian ovum has been experimentally determined in only a few rodents, carnivores, and ungulates (Table 14.6). In the ferret, for example, Hammond and Walton (1934) found that the ovum remains capable of fertilization for not more than 30 hours after ovulation. In the rabbit, delay in fertilization
results in lowered fertility and smaller size of litters (Hammond, 1934). In the hamster 50 per cent of ova are incapable of fertilization 4 to 5 hours after ovvdation (Chang and Fernandez-Cano, 19581.
In rats the spermatozoa may penetrate eggs which have been aged 12 hours before fertilization or to a point of devitalization but not of death. In such eggs they may even undergo transformation into the male pronuclei and form segmentation spindles, but the female nucleus in the same egg either fails to develoj) or fragments into a number of nuclei of varying sizes. Even though 70 per cent of the greatly over-ripe rat eggs may be penetrated by spermatozoa, various abnormalities of development result which are not compatible with continued growtii and development. Thus, at the time of implantation only 4 per cent of the experimental rats are impregnated. Furthermore, the ova which do implant successfully are retarded in their development, and the
«50
SPERM, OVA, AND PREGNANCY
majority die before the fetal period is reached (Blandau, 1952; also see Braden, 1959).
A strikingly similar picture is presented by delayed fertilization in the guinea pig. The fertilizable life of the egg in this species is approximately twice (20 hours) that of the rat (Blandau and Young, 1939; Rowlands, 1957). The first effects of over-ripeness are seen in embryos from females inseminated approximately 8 hours after ovulation. No normal development followed inseminations more than 20 liours after ovulation. As far as could be determined, the principal effects of aging were either the early death of the zygote in the pre-implantation period or retardation in the rate of growth in embryos which were capable
of implanting. A moderate delay in fertilization has been shown to lead to polyspermy particularly in rats and rabbits (Austin and Braden, 1953; Odor and Blandau, 1956).
M. IMPLANTATION
The blastula of the placental mammal is called the blastocyst. In the fully developed stage it is still enclosed in the zona pellucida and shows the inner cell-mass attached to the embryonic pole of the trophoblast. During the early period of its existence the blastocyst is spherical to somewhat oval in shai)e and except for size appears remarkably similar from animal to animal (Fig. 14.i7).
In most mammals, the blastocyst does not come into firm contact with the maternal
.•^ ^.
Fig. 14.17. The similarity of the free uterine bhistoc-y.^t.s of various mammals: 1, 5!/2-day
human blastocyst (photograph courtesy, Hertig, A., and Rock, J.); 2, 6-day guinea pig blastocyst; 3, 9-day monkey blastocyst (Heuser and Streeter, 1941); and 4, 9-day sheep blastocyst (Boyd and Hamilton, 1952).
BIOLOGY OF EGGS AND IMPLANTATION
851
endometrium for a number of days after reaching the uterus. In the mouse, mole, shrew, and guinea pig, the free uterine period is from 3 to SVk days; in the rabbit, 5 to 6 days; in the rhesus monkey and possibly the human, 4 to 6 days ; in the cat, 8 to 9 days; in the dog, 9 to 10 days; and in the ungulates probably somewhat longer.
Under the conditions of "developmental diapause" or delayed implantation, the free uterine period of the blastocysts may be significantly prolonged. Delayed implantation occurs naturally in a variety of species such as the pine marten, 6 months; American badger, 2 months; European badger, 3 to 10 months; European roe deer, 4 months; armadillo, 14 weeks; fishers, 9 months; and bears, 6 months. Delayed implantation has also been recorded in the stoat, weasel, sable, and fur seal. In the rat, mouse, and certain insectivores, implantation may be delayed several days to 2 wrecks if there is concurrent lactation (Lataste, 1887; Daniel, 1910; King, 1913; Hamlett, 1935; Brambell, 1937; AVeichert, 1940, 1942). In the mouse and rat the delay varies roughly with the number of young suckled, and this, in turn, prolongs the period of gestation. According to Lataste, the duration of gestation is normal in mice suckling only 1 or 2 young but prolonged in those suckHng 3 or more. If certain hormonal conditions are satisfied, implantation will occur in normal females suckling large litters (Kirkham, 1916; Weichert, 1940, 1942, 1943; Krehbicl, 1941). Delay of implantation is very likely due to an inhibitory effect by some uterine or nutritional factor acting on the blastocysts (Whitten, 1958). Various experimental methods may successfully delay implantation without destroying the ova. Ovariectomy the second day after mating in the rat, followed by subliminal doses of progesterone (0.5 mg. per day ) , will keep the eggs alive for 6 to 45 days, but the decidual cell response and implantation do not take place. If more progesterone than 0.5 mg. per day is injected into these animals, implantation may occur. A combination of injections in which a small dose of estradiol benzoate is added to the subliminal dose of progesterone is very effective in consummating iml^lantation. In contrast, if the ovaries are removed from pregnant rats on the fourth
day when the blastocysts have reached the cornua, progesterone, even in dosages of 10 mg., cannot effect implantation. If estrogen and progesterone are injected simultaneously, the blastocysts will resume their growth and will implant (Canivenc and Laffargue, 1957; Cochrane and Meyer, 1957; Mayer, 1959).
The blastocysts of pregnant rats spayed the 4th day may remain alive for as long as or longer than 21 days. Rat blastocysts apparently do not reciuire adrenocortical hormones to remain viable. Mayer (1959) and his co-workers have demonstrated that the blastocysts in the cornua of rats which have been ovariectomized and adrenalectomized on the 4th day after mating can implant on the 10th day, provided estrogen and progesterone are both injected simultaneously.
The experiments of Cochrane and Meyer, and others that have been mentioned, suggest that the optimal conditions for embryo attachment and implantation depend on a delicately balanced, synergistic action of estrogen and progesterone on the endometrium. But nothing is known as to what is happening within the egg during its dormant state and what factors control the dormancy, nor do we understand what changes occur within the uterine lumen which may eventually satisfy the conditions of the embryo to continue its growth, make attachment to the uterine epithelium, and implant. Our point of view will no doubt be broadened as experimental approaches to the problem are varied and more species are studied.
Runner <1947), Fawcett (1950), and Kirby (1960) found tliat, irrespective of the state of the host's gonads, implantation occurred when mouse ova were transplanted either to the kidney capsule or to the anterior chamber of the eye. Whitten (1958) transplanted 8-celled mouse eggs to the surface of the kidneys of normal and hypophysectomized mice. Ten days later successful grafts were found in 10 of 15 normal and in 13 of 18 hypophysectomized animals. Successful implantation of mouse eggs onto the kidney apparently does not depend on the secretion of the pituitary.
Buchanan, Enders and Talmage (1956)
852
SPERM, OVA, AND PREGNANCY
reported that implantation occurs in ovariectomized armadillos that are not receiving hormonal replacement. In the European badger ovulation occurs during delayed implantation. The new set of corpora lutea does not hasten implantation because delay in implantation may continue for 2 months after the last ovulation (Harrison and Neal, 1959).
The phenomenon of delayed implantation offers an excellent experimental approach to the general problem of embryo-endometrial interrelationships and the specific factors that control embryo attachment and implantation.
N. SPACING AND ORIENTATION OF OVA 7^- UTERO
The specific sites of implantation in mammals having multiple young, as related both to the longitudinal axis and to the surface of the endometrium, are remarkably constant (Mossman, 1937). Even in animals having only a single young and a simplex uterus, such as man, monkey, sloths, and others, the location of the implantation site and the orientation of the blastocyst to the endometrium are quite definitely regulated (Mossman, 1937; Heuser and Streeter, 1941).
Various explanations have been proposed to account for the intra-uterine spacing of blastocysts in polytocous mammals. Mossman suggested that the implanting blastocyst may interact in some manner with the surrounding endometrium so as to create a local refractory zone in which no other embryos can implant. The results obtained by Fawcett, Wislocki and Waldo (1947) after transplanting several mouse ova into the same anterior chamber of the eye are of interest in this connection. They found that fertilized eggs continue to develop in close proximity to one another only until one of them begins to implant. Thereafter, the remaining embryos degenerate. The onset of the degenerative changes in the surrounding blastocysts is coincident with the extravasation of blood into the tissues in the immediate vicinity of the attaching embryo. They suggest that possibly a cytolytic ferment of the trophoblast may cause edema or hemorrhage into the maternal tissues which so al
ters the local environment that it is untenable for the remaining blastocysts.
According to Mossman's theory, the blastocyst that enters the uterine cavity first establishes a refractory zone near the uterotubal junction and begins the process of attachment. The remaining blastocysts establish similar zones in the fashion of a gradient toward the cervix until all become evenly spaced. It has been frequently observed in pregnant animals with bicornuate uteri that the embryos which are implanted nearest the oviducts are slightly more advanced in development than those nearest the cervix. It has also been observed that the embryos which are implanted nearest the cervix show a higher incidence of resorption than those implanted at other sites.
Recently McLaren and Michie (1959) have taken issue with Mossman's theory that implantation is serial and that refractory zones are established. These investigators induced ovulation and mating in mice by hormone treatment. At 18V^ days after mating, the cornua were divided into 6 equal segments and the embryos weighed. They found that the embryos in the middle of the cornua actually weighed less, on the average, than those at either end. The embryo lying nearest the oviduct was usually significantly lighter than its neighbor.
It may be questioned whether the differences in weight of mice fetuses at ISV^ days post coitum have any relationship to differences in size and differentiation of the embryos during the first 5 to 10 days of development or during the period of orientation in utero or of attachment and implantation.
Investigators who have observed blastocysts and implanting embryos have frequently commented on the variations in the early stages of development in the same animal and the variation from animal to animal when they are killed at identical times after mating. The variations in the rate of differentiation are particularly striking if the development of the attachment cones of the guinea pig embryos are observed in tissue culture. The attachment cones of each of the 2 to 3 blastocysts recovered from the cornua of the same animal may be in a different stage of development and may retain
BIOLOGY OF EGGS AND IMPLANTATION
853
this difference throughout the period of cultivation.
The successful transplantation of eggs from animal to animal in certain rodents is feasible and may be the means whereby an experimental approach to the problem of spacing can be made. One or more fertilized eggs could be transferred to the oviducts of properly timed hosts and their sites of attachment observed. One of the problems in evaluating implantation grossly in transplantation e.xperiments is the possibility of inert objects (lint, clumps of cells, etc.) affecting the decidual response and mimicking imiilantation.
In normal, pregnant rats the embryos are more evenly spaced in cornu when the number of young is 5 or more. If the number of implanting blastocysts is less than 4, there is a tendency to occupy chiefly the caudal halves of the horns (Frazer, 1955).
Information is needed as to the manner in which eggs enter the cornua, i.e., whether they enter singly or as a group and what the relationship of the multiple eggs may be one to another during the several days that they lie free within the uterine lumen. It is ciuite clear that embryonic spacing in utero is more even than random. This raises the cjuestion as to what controls the size of the refractory area if the cornu is crowded by superovulation, transplantation of eggs, or more than normal numbers of eggs from compensatory hypertrophy in cases where one ovary has been removed.
It has long been known that in bicornuate uteri blastocysts may pass from one cornu into the other through the body of the uterus (Boyd, Hamilton and Hammond, 1944; Boyd and Hamilton, 1952; and many others). Bischoft' (1845) interpreted transuterine migration as a method by which the distribution of embiyos could be equalized in cases where there is a disparity in the number of eggs ovulated from each ovary. The means by which this migration is accomplished has been the subject of speculation and some investigation.
At present, there is no direct evidence that the unimplanted embryo has the power of independent movement. If this is true then the positioning of the blastocyst in utero and its orientation in relation to the endo
metrium must depend on chemical and/or
physical forces. Markee and Hinsey (1933)
suggested that alternate contractions of the
cornu transport blastocysts from one to another. Krehbiel (1946) anastomosed the
cornua of ovariectomized rats in a variety
of ways and concluded that each uterine
cornua retains its individuality in effecting:
the distribution of embryos.
The role of the myometrium in the distribution and spacing of the blastocysts in utero has received considerable attention. Corner (1923) and Wislocki and Guttmacher (1924) found active myometrial contractions in the sow during the preimplantation period. Even though the postovulatory contractions occurred with greater frequency, they were greatly diminished in amplitude compared with those recorded during the estrous phase. The motility pattern of the myometrium changes gradually from day to day so that, by the time of implantation (12th or 13th day), the spontaneous contractions continue at a rate of 4 to 8 per minute, but their amplitude is so slight that the kymographic tracings are almost level. Similar observations were reported for the excised uterine horns of the rabbit (Knaus, 1927). Using a more refined technique and beginning their observations immediately after the muscle strips were put into the bath, Csapo and Corner (1951) and Csapo (1955) showed that uterine muscle under the dominance of progesterone displays a high state of irritability but poor conduction, and it develops spontaneously a state of "contracture" when it is first placed in the muscle bath. Spontaneous contractions begin after a short interval but they are of very low amplitude. The initial "contracture" is reversible and may be suspended by electrical stimulation or anoxia. Progesterone in some way alters the response of the myometrium to stimuli.
The motility pattern of the myometrium under the dominance of progesterone is certainly different from that when the animal is in estrus, but the nature of these differences is still puzzling (Reynolds, 1949; Csapo and Goodall, 1954). A strip from an estrous uterus placed in the bath relaxes immediately. After a short interval, spontaneous contractions begin and continue
854
SPERM, OVA, AND PREGNANCY
with increasing amplitude. Thereafter, contractions occur at intervals of 1 to 2 minutes followed by prompt relaxation. In contrast, similar relaxation was not observed in uterine strips under the influence of progesterone. Instead they slowly shorten.
Ivy, Hartman and Koff (1931j observed that muscular contraction waves in the monkey uterus originate from an area slightly ventral and cranial to the insertions of each of the oviducts and then proceed medially to meet in the midline. They concluded that in the monkey the area of the endometrium where implantation usually occurs is affected by contractions to a lesser extent than the remainder of the uterus.
Nicholas (1936) interposed a section of duodenum into the rat's uterus and found embryos in the lower uterine segment. Lim and Chao (1927) reversed the middle portion of one or both cornua of the rabbit and reported that pregnancy was not prevented.
Markee (1944) introduced sea urchin eggs, celloidin balls, and glass beads into the tubal ends of rabbit cornua and observed their distribution at varying intervals from estrus to 10 days after ovulation. He found that the sea urchin eggs were distributed most evenly in the uteri of cstrous rabbits, especially at the time of ovulation. Fairly good distribution was recorded at 5 days and poor distribution at 10 days after ovulation. As noted below, none of these inert objects or sea urchin eggs expand with time as do rabbit blastocysts before attachment. It is doubtful that the movements of these objects in utero could be considered as the normal state of affairs in the transport of blastocysts. In order to study this problem further, Markee observed uterine contractions directly through a glass window which had been sewn into the abdominal wall. Three types of contractions were observed during estrus and for 5 days after ovulation : (1) local ring-type contractions persisting for approximately 10 seconds, (2) peristaltic contractions proceeding throughout the length of the cornu, and (3) antiperistaltic waves of approximately the same intensity as the peristaltic contractions. After the 5th day, the peristaltic and antiperistaltic contractions decreased greatly in amplitude and in the length of their excursions.
Recent studies on the mechanisms contributing to the distribution of the implanting rabbit blastocysts have directed attention to the possibility that both physical and chemical interactions between the blastocyst and uterus are important (Boving, 1952a, b, 1954, 1956, 1959). Boving has found that by 7 days post coitum, rabbit blastocysts have achieved an almost even distribution, not only with reference to the space between them, but also with respect to the entire length of the uterine cornu (Fig. 14.18). If the number of blastocysts in utero varies, the spacing is nevertheless appropriate to their number. The cornua reacts to the presence of each blastocyst and positions it in relation to all other blastocysts present until a remarkably even distribution is achieved by the 7th day post coitum. There is evidence from the work on the rabbit at least that the movement and i)ositioning of blastocysts in utero coincide with their increase in size. Rabbit blastocysts of approximately 1-mm. size are propelled much more slowly than blastocysts or glass beads 3 to 6 mm. in diameter. Boving suggested that each blastocyst acts as a localized stimulus which initiates the propulsive muscular activity and that the size of the blastocysts determines the way in which the myometrium responds. Cessation of positioning is coincident with a local loss of uterine tone and a ballooning out of the antimesometrial wall to form a "dome."
The blastocysts of the leporid family of rodents, the carnivores, some insectivores, and bats undergo considerable expansion in the uterine cavity before and at the time of attachment. In these animals, then, the spacing of the blastocysts may be arranged according to Boving's theory that myogenic uterine contraction is the effector of both propulsion and spacing.
As mentioned earlier, during the 6th and 7th days after copulation in rabbits, the expanded blastocysts occupy a distended, antimesometrial "dome" caused by a local decrease in uterine muscle tone. From in vivo observations of the pregnant uterus, Boving (1952b, c) observed that the blastocysts of the rabbit undergo a rotational
BIOLOGY OF EGGS AND IMPLANTATION
855
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••
.^
...
t
1
1 1
1
1
20
TUBAL END
7
'a
40 60 80
OF UTERINE LENGTH
100
Fig. 14.18. Positions of rabbit blastocysts (dots) in utero (bars) from the 3rd to the 8th day post coitum. There is little change in position during days 3 and 4. Even distribution is achieved 6 to 7 days -post coitum. The crosses in the 8-day uterine horn represent the position of blastocyst models which had been in the uterus for 2 days (Boving, 1954).
and to-and-fro motion approximately every 30 seconds. This seems to be effected by a change in the tone of the muscles forming the uterine dome. The rotational motion could provide an orientational mechanism, because eventually all surfaces of the blastocyst would come in contact with the dome. In the in vivo observations, it seemed that the blastocyst is "grasped" by the muscular action of the uterus, and by the 7th day post coitum is confined along the antimesometrial border.
As implied earlier, the orientation of the blastocyst with reference to the uterus and mesometrium varies considerably in different species. It may be mesometrial as in the Pteropodidae and Tarsiidae, antimesometrial as in most rodents and insectivores, or orthomesometrial as in the Centetes and Hemicentetes (Mossman, 1937).
The orientation of the embryonic disk within the uterus is remarkably constant in closely related species but varies greatly in different orders. Thus the inner cell mass at the time of attachment may be directed toward the mesometrium in the rodents, toward the antimesometrial side in the vesperilionid bats and some insectivores, or toward the lateral side as in the golden mole. With the possible exception of the
rabbit and guinea pig, the role of the blastocyst in determining the pole of attachment is unknown.
Alden (1945) reversed the mesometrialantimesometrial axis of the uterus of the rat by surgical means and demonstrated that, regardless of the position of the altered segment, the implanting embryos were correctly oriented relative to the uterus. Apparently, gravity alone is not of great importance in determining the pole of attachment, at least not for the rat egg.
Before the cells of the trophoblast can come into contact with the uterine epithelium, either the tough and resistant zona pellucida must be removed or the cells of the living trophoblast must penetrate the zona. A number of investigators have thought chiefly in terms of the removal of the mucous coat and zona pellucida by uterine factors. As we will see, others have been impressed by the possibility of participation by the trophoblast.
In 1935 Hall presented evidence which seemed to support the former view. He found that in rats and mice the zonae pellucidae disappear rapidly when immersed in fluids of pH 3.7 or below. In less acid solutions (pH 4 to 5), they were affected much more slowly. Acidified Ring
856
SPERM, OVA, AND PREGNANCY
er's fluid at first caused a swelling of the zonae, and the ordinarily smooth outer contour became wavy and fringe-like. In measuring the hydrogen ion concentration of the fluids in the vicinity of deciduomata of the rat, values as low as pH 5.7 were recorded. Such values w^ere of sufficient acidity to effect the gradual softening of the zona pellucida. Pincus and Enzmann (1936) also measured the pH of uterine luminal fluids in pseudopregnant rats and at no time observed values below 6.7. From Hall's work it was concluded that "as the decidua develops around the implanting egg and as the metabolic activities of the dividing blastocyst increase, the fluid bathing the blastocyst may become sufficiently acid to be a factor in the removal of the oolemma." Fertilized mouse ova, transplanted to the anterior chamber of the eye, lost their zonae independently of a change in hydrogen ion concentration of the environmental fluids <Fawcett. Wislocki and
Waldo, 1917). Other factors which alter the physical properties of the secondary and tertiary membranes were described earlier. At this point, how^ever, it is important to direct attention to LutwakMann's (1959) recent comments on the toughness and resilience of the zona in the rabbit and the difficulty in dissolving it except by harsh enzyme and chemical means. Results obtained during work on the guinea pig and rabbit have prompted investigators to think of other methods by which the zona pellucida and other investing membranes might be shed. Remnants of the zona pellucida have been found adhering to the blastocyst wall in sections of early implanting guinea pig ova (von Spee, 1901; Maclaren and Bryce, 1933). This fact indicates that the zona pellucida is not uniformly lost by chemical action of the fluids of the uterus. In the guinea pig the abembryonal pole of the blastocyst first makes contact with the endometrial
Fig. 14.19. Photomicrograph of a living guinea pig blastocyst removed on the 6th day after
ovulation. The inner cell mass is directed towards the top of the page. Abembryonal cells
form but a single layer (compare with Figure 14.17, 2). X 900.
BIOLOGY OF EGGS AND IMPLANTATION
857
epithelium of the antimesometrial border of the cornu. In 1883 von Spee described an increase in the size and number of the abembryonal pole cells of the guinea pig shortly before implantation of the blastocyst and gave an account of the pseudol)odia-like processes of these cells penetrating the zona. These processes were regarded by other investigators as fixation artifacts or "as of the nature of a secretion" (Sansom and Hill, 1931). Recently, the early iml)lantation of the guinea pig has been reinvestigated and the observations of van Spee have been confirmed (Blandau, 1949b). It is remarkable that there should be so little change in the zona of the guinea pig egg during its 3 day sojourn in the cornu. The blastocyst completely fills the perivitelline sjiace and the abembryonal pole cells comprise but a single
layer (Fig. 14.19). Within a few hours before the ovum attaches itself to the uterine epithelium, the abembryonal pole cells proliferate to form the implantation cone. The trophoblast cells lying next to the zona send numerous slender protoplasmic processes through it (Fig. 14.20) until the abembryonal pole is riddled with them. The cytoplasmic extensions increase rapidly in size and may extend as bulbous expansions of varying shape for some distance beyond the zona pellucida (Fig. 14.21). It is only in the region where the zona is perforated by the extension of the abembryonal pole cells that it gradually becomes thinner and disappears. The remainder of the zona pellucida has been observed in vitro to slough off from the attaching blastocyst, much as a grape skin is removed from the flesh of the grape. Attachment cones have been de
FiG. 14.20. AiiiK-aiaiicc of li\iiig guinea pig l)la.'<tiicysi api>r()xiiiiaii'l\- oiic hour before attachment of the abembryonal pole to the endometrium. Note the increase in the number of the abembryonal pole cells and the cytoplasmic extensions of these cells through the zona pellucida. X900.
858
SPERM, OVA, AND PREGNANCY
Fig. 14.21. Living guinea pig blastocyst removed appioximatel}' one-half hour before attachment to the endometrium. The blastocyst is slightly rotated to show the extensive protoplasmic projections at the abembryonal pole. X 900.
scribed in fixed preparations of a number of genera of grovnid squirrels and chipmunks (Lee, 1903; Mossman, 1937). Although the extension of conclusions based on the study of one species to other species is precarious, it is possible that the same relationship of the attachment cone to the zona pellucida exists in other forms (Mossman, 1937). Boving noted a change in the viscosity and adhesiveness of the rabbit egg investments at the time of implantation which he attributed to local alkalinity (pH 9) released from one or more regions of the abembryonic hemisphere. Following adhesion, the outer investments of the blastocyst in this area disintegrate. Inasmuch as remnants of the membranes are sometimes observed in the areas between the implanting blastocysts, their final removal ap
jiarently is similar to that described for the
guinea pig. When the membranes have been
shed the abembryonic trophoblast adheres
to the uterine epithelium, particularly in
areas where blood vessels are subjacent
to the epithelium. The trophoblast penetrates the epithelium by displacement, and
the invasion of the stroma at first is not
destructive.
O. BLASTOCYST EXP.\XSION
In the guinea pig, rat, mouse, and hamster, the diameter of the blastocyst at the time of attachment is approximately the same as that of the tubal ova. In these species implantations are more or less regularly spaced but not invariably so, because placental fusion occurs frequently. Thus there does not seem to be the same purpose
BIOLOGY OF EGGS AND IMPLANTATION
859
fill interplay between the embryos and cornua as described for the rabbit. The blastocysts of these rodents are definitely polarized in relation to the uterine epithelium at the time of attachment and invasion. Although it is universally stated that the blastocyst does not have the cal^acity for independent movement in utero, observations on the behavior of the guinea pig blastocyst in tissue culture and the cytologic descriptions of the attachment cones in the monkey, ground squirrels, and chipmunks suggest that the blastocyst plays an active role in its positioning at the time of attachment. This possibility would encourage one to examine more carefully the living blastocysts of various animals at the time of attachment. From some of the earlier investigations, it would seem that the expansion of the rabbit blastocyst is dependent on physiologic factors external to the egg itself (Pincus and Werthessen, 1938). Thus, blastocyst expansion is interfered with if ovariectomy is performed or estrogen is injected 3 to 5 days after mating. On the other hand, injections of progesterone can reverse the effect of estrogen (Burdick and Pincus, 1935; Pincus, 1936; Pincus and Kirsch, 1936). Allen and Corner (1929) showed that if progesterone is injected into rabbits ovariectomized shortly after fertilization, the fertilized eggs will implant normally. If fertilized rabbit ova are grown in watch glass cultures, they will ■ cleave normally, but they herniate and collapse during the blastocyst stage (Lewis and Gregory, 1929) . If crystalline progesterone is added to these cultures, there is no increase in the rate of cleavage nor is herniation or collapse prevented (Pincus and Werthessen, 1937). The same investigators have shown that regular expansion of the blastocyst is obtained if the morulae or blastocysts are cultured in homologous serum and the medium is continually circulated. Recently, Bishop observed that expansion is suppressed if the oviducts of rabbits are ligated soon after the blastocysts have entered the uterus. The implication is that some oviducal factor is necessary for expansion. The problem is complicated by the fact that the egg does not expand during its 3 day sojourn in the oviduct.
From the observations recorded above, it seems that in order to stimulate normal growth and expansion of the blastocyst, in the leporid family of rodents at least, progesterone must act in some way on oviducal and uterine metabolism since both parts of the genital tract are probably involved.
The specific physicochemical processes in blastocyst expansion are not known. A plausible explanation is that the expansion may be due simply to the processes of osmosis, the changes in size being related to ionic variations of the fluid within the blastocyst cavity and the surrounding environment. It is more likely, however, that comjMex processes of active transport are involved, and, if these are to be elucidated, help from the biochemist and physical chemist is essential.
One of the difficulties confronting investigators so trained is the small amount of material obtainable for study by the conventional chemical methods. This is particularly true in such laboratory animals as the mouse, rat, hamster, guinea pig, and monkey, in which the blastocyst undergoes very little expansion before implantation and in which uterine secretions are present in very minute amounts. Nevertheless the recent approaches to the study of embryo attachment and implantation in the rabbit, particularly those by Boving (1954), Bennett (1956) and Lutwak-Mann (1959), offer a methodological approach that is essential if the dynamic aspects of nidation are to be understood. Lutwak-Mann especially and her co-workers have been the most active in discerning the practical problems in the handling of early embryologic material for biochemical study and in devising sound methodologic approaches.
In 1938 Pincus and Werthessen described a crystalline deposit in the abembryonal membranes of certain blastocysts of rabbits removed on the 5th day after mating from females which had been ovariectomized 18 to 20 hours after copulation. Boving (1954) identified this crystalline material as calcium carbonate and noted that there is little or none present 3 to 4 days after mating, but that the deposit increases to a maximum at the 6th day post coitum. He suggested that the osmotic effect of the blastocyst fluid is increased by the ionization of the inherent calcium carbonate reserve. Deficient respiration of the free blastocyst may perhaps lead to the production of acids which react with the calcium carbonate reserve. At the time of uterine attachment, there is improved gas exchange due to the embryo's close proximity to subepithelial blood vessels. Thus the bound alkali is liberated, the ionic concentration of the fluid is decreased, and blastocyst turgidity is lessened.
In measuring the bicarbonate of the rabbit blastocyst cavity fluid, Lutwak-Mann and Laser (1954) found a remarkably high content in 6- and 7-day-old embryos. Thereafter, the level of bicarbonate fell rapidly so that on the 8th day, when implantation is completed, the level was somewhat below that for maternal blood. The occurrence of high concentrations of bicarbonate in the unattached blastocysts led to assays of carbonic anhydrase activity in extracts of pregnant and nonpregnant rabbit uterine mucosa. It was found that carbonic anhydrase activity was very low in the uteri from nonpregnant animals but very high in the uteri from pregnant individuals. The oviducts, endometrium, and placental tissues are the main loci of carbonic anhydrase activity in the female reproductive tract. There are, however, species differences in the extent and the time at w^hich the enzyme can be demonstrated. The endometria of pregnant or nonpregnant hamsters, rats, and guinea pigs do not contain measurable quantities of carbonic anhydrase. However, significant enzyme activity has been found in the maternal portions of the placenta of these animals (Lutwak-Mann, 1955).
It has been clearly established for the rabbit that the enzyme is hormone-dependent. Progesterone and progesterone-like compounds greatly increase the amounts of the enzyme measured in the endometrium and this increase is proportional to the dosage of the hormone injected. There is no concomitant increase of carbonic anhydrase in the blood (Lutwak-IVIann and Adams, 1957a, b).
There is a 10- to 30-fold increase in the weight of the blastocyst between the 5th and 6th days. Dry weight measurements have shown that this increase is due primarily to water. The enzyme system responsible for the active transport of water is as yet unknown, but is being actively sought. Concentrations of Na, K, and CI ions in the yolk sac fluid approach or, in the case of K, exceed that of the maternal serum. Glucose, on the other hand, is present in less than half the amount found in maternal blood on the 7th day and two-thirds the amount on the 8th day. Data are also available on total nitrogen, phosphorus, bicarbonate, and various vitamins, particularly the components of the B complex, in the unimplanted blastocyst (Kodicek and Lutwak-Mann, 1957; Lutwak-Mann, 1959). Obviously the opportunities for utihzing isotopes for transfer studies in the fresh and implanting blastocysts are many indeed, and one may confidently expect a rapid unravelling of the manifold functional aspects of implantation if these techniques are employed by competent investigators.
P. Embryo-Endometrial Relationships
The interrelationship between the blastocyst and the endometrium at the time of attachment and implantation is not only exceedingly complex but also highly variable in different species. Irrespective of the complexity of the attachment, each type has as its purpose the apposition or intimate fusion of the fetal membranes to the maternal endometrial epithelium or stroma so that adequate physiologic exchange can take place.
Earlier studies on the experimental production of deciduomas by mechanical stimulation of the sensitized endometrium, and the dependence of implantation on the proper hormonal stimulation of the uterine mucosa, had the effect of swinging the pendulum of opinion toward the endometrium as being the most active agent in the process of nidation (Huber, 1915; Kirkham, 1916; Selye and McKeown, 1935; Krehbiel, 1937; Rossman, 1940). More recently, however, the observations ( 1 ) on the development of the attachment cone in some specific area of the trophoblastic wall just before attachment, (2) the changes in the viscosity and adhesiveness of the egg envelopes at the time of attachment, and on the developmental potentialities of ova transplanted to the anterior chamber of the eye and other sites have swung the pendulum back to the embryo and the role that it may l)lay in nidation (Asshcton, 1894; von Spec, 1901; Schoenfeld, 1903; Mossman, 1937; Fawcett, Wislocki and Waldo, 1947; Runner, 1947; Blandau, 1949a; and Boving, 1954, 1961 j.
The extensive i)rolil'eralion and differentiation in the endometrium of certain animals after ovulation undoubtedly arc iml)ortant in the nourishment and maintenance of the ovum in utero and in providing a suitable implantation site. The considerable growth and differentiation which the blastocysts of many animals undergo before they make contact with the uterine mucosa would indicate that more nutrients are required than are stored in the ooplasm of most mammalian eggs. The widespread occurrence of glucose, glycogen, lipids, phosphatases, iron, calcium, and many other substances, including vitamins and enzymes, in the endometrium may provide the necessary nourishment during the very early stages of implantation ( Wislocki and Dempsey, 1945) . Bloch (1939) described the secretion of an osmol)hilic substance by the uterine epithelium which is thought to be absorbed by the free mouse blastocyst. The work of Daron (1936), Markee (1940), Phelps (1946), Parry (1950), and Boving (1952a, 1961) has demonstrated that there is an increased blood supply immediately below the uterine epithelium at about the time of blastocyst attachment. The increased vascularity may not only provide nutrition to the uterine epithelium, but more importantly it provides blood vessels for specific physicochemical reactions between the trophoblast and endometrium (Boving, 1959a) . A similar increase in the blood supply in the antimesometrial area has been observed in the guinea pig (Bacsich and Wyburn, 1940). This is the area in which implantation invariably occurs in this species, and the localized hyperemia is considered to be a factor in tlie antimesometrial implantation.
It is well established that the presence of an actively secreting corpus luteum is essential if implantation is to be complete and successfully maintained. In rabbits progesterone is necessary, not only for the nutrition of the free blastocyst in utero, but also for implantation (Fraenkel, 1903; Corner, 1928b; Corner and Allen, 1929; Hafez and Pincus, 1956a, b) . Histochemical and quantitative tests have indicated that lipids are present in the endometrium in greater amounts during the luteal phase of the reproductive cycle than at any other time (Krehl)iel, 1937; van Dyke and Chen, 1940; Alden, 1947).
It is clear that the presence of an embryo in the cornu exerts a significant effect on the secretion of luteotrophic hormone and on the functional life of the corpus luteum. How these effects are producecl remains a challenging problem. We need to determine whether direct invasion of the endometrium is essential or whether mere expansion of the embryo can act as a trigger mechanism. Nalbandov and St. Clair (1958) have shown that if plastic beads of more than 2 mm. in diameter are inserted into the cornua on the 8th day of the estrous cycle in sheep, the cycle is significantly lengthened. Denervation of the cornu containing the beads prevented this change in length.
It has been found repeatedly that endometrial sensitivity to the formation of deciduomata is limited normally to the period of implantation and placentation (Loeb, 1908; Allen, 1931; Selye and McKeown, 1935; Krehbiel, 1937; Greenwald, 1958b). The traumatizing substances were physical, chemical, and electrical stimuli. From these studies, three facts were revealed: (1) The formation of the "maternal placenta" can be induced in the complete absence of the blastocyst (Krehbiel, 1937; Mossman, 1937; Dawson and Kosters, 1944). (2) Even though tissue destruction in the endometrium can be brought about by specific and nonspecific stimuli and even though the endresult may appear similar, the mechanisms producing the changes do not necessarily stem from the same basic stimulus. (3) All of the stimuli used are presumed to have as the basis of their action some kind of tissue injury.^ Notwithstanding, the histologic transformations of the deciduomas correspond exactly to those occurring normally in
^ The passage of an electric current of sufficient magnitude through the endometrium to induce the decidual response gives no evidence of tissue damage that can be detected microscopically. This of course does not eliminate the possibility^ that cellular injury has not occurred.
early pregnancy. Krehbiel (1937) found, for
example, in the experimentally induced deciduomas of the rat that glycogen and lipids
appeared intracellularly in cells which cytologically seemed identical with those of the
normal endometrium of pregnancy.
It would be interesting to know whether the same intensity of artificial stimulus would induce the decidual response in the uteri of a variety of animals. In the rat, for example, the slightest pressure against the superficial uterine epithelium, at the proper time after ovulation, is sufficient to initiate the decidual response. Thus a bit of lint, small clumps of cells, and glass or paraffin beads the approximate size of eggs effect an endometrial response identical with the response to the normally implanting embryo (Blandau, 1949a). In this species the very earliest changes in the subepithelial stroma begin when the blastocyst is attached only very tenuously to the uterine epithelium (Fig. 14.22). From this response of the endometrium, perhaps localized pressure is sufficient to induce the decidual reaction. Equally impressive is the fact that the decidual response begins before there is any alteration in the superficial uterine epithe
Fig. 11.22. I.MiigiiiKhii.il ^.riinn 1 hrough the antimesometiial wall of a pregnant rat killed on the 5th day. The loosely attached rat blastocyst has initiated the subepitheUal decidual response. There is no detectable alteration in the superficial epithelium. X 450.
limn detectable by microscopic means. Thus, any stimulus from living eggs or inert objects within the lumen is transmitted to the underlying stroma directly through the intact lining epithelium. Wimsatt (1944), in describing the earliest phases of implantation in the bat, came to the conclusion that the changes in the epithelium of the pocket into which the blastocyst comes to rest is "an expression of a localized physiologic reaction of the uterus to some chemical stimulus of unknown nature liberated by the ovum, which may produce this effect by acting locally on the epithelium or by inducing a local relaxation in the uterine muscle."
It is important to recall again that the destruction and removal of the uterine epithelium by the trophoblastic cells of the rat blastocyst do not begin until the embryo lies deeply within the decidual crypt and a sizable decidual response has been elicited (Alden, 1948). Therefore, the initiation of the decidual reaction and the active invasion of the endometrium by the trophoblast are two distinctly different phenomena separated by a considerable interval of time. In the guinea pig, rabbit, monkey, man, and possibly other mammals, the normal decidual response is not elicited until the embryo has effected the removal of the sujierficial uterine epithelium. Recently, it has been shown that there is a definite species difference in the response of the endometrium to glass or paraffin beads inserted into the uterus of properly timed females (Blandau, 1949a). In the rat, the beads initiated the decidual response and were implanted in a manner similar to blastocysts. In the guinea pig, the beads did not effect the removal of the uterine epithelium, and only occasionally was a minimal decidual response induced. Thus it would appear for the guinea pig, at least, not only that the .stimulus must be a direct one to the underlying stroma but that a certain amount of tissue injury or invasion is necessary before the decidual response can be initiated.
As we suggested earlier, the initiation of the decidual reaction may be the result of a localized pressure exerted by the blastocyst, or of the action of some chemical substance secreted by the egg, which is transmitted to a properly sensitized subepithelial stroma. Recently, Shelesnyak (1952, 1954, 1959a, 19591) I undertook to investigate the nature of the non-specific stimulus required to initiate the deciduomas by determining the effects of histamine and histamine antagonists on the endometrium. He theorized that some degree of injury was a common factor to all methods of uterine stimulation, that a histamine or histamine-like substance was present at the site of injury, and further, that at the time of blastocyst attachment there is an "estrogen surge" which acts to release histamine from the endometrium and which in turn initiates the decidual cell response. Evidence for the role of histamine in deciduoma production also includes the depletion of the mast cell population of the endometrium just before attachment. On this basis, after instilling diphenhydramine hydrochloride or other antihistamines into one horn, both cornua of pseudopregnant rats were stimulated to induce deciduoma development. Definite inhibition of deciduoma was noted in the cornu receiving the antihistamine, particularly if the drug was instilled before the transformation of endometrial cells to decidual cells. Consistent with this finding are the indications from extensive tests that drugs having a specific histamine antagonism are effective in suppressing the decidual cell reaction when introduced into the uterine lumen of rats and mice during pseudopregnancy. On the other hand, antihistamines injected subcutaneously in these animals ordinarily fail to prevent implantation. Species differences must also be considered. Boving (1959) was unable to find mast cells associated with rabbit trophoblast invasion.
The theory that some mechanism of histamine release is responsible for initiating the decidual cell reaction would logically imply that the blastocyst is an active histamine secretor or that it indirectly effects a rise of "free" histamine in the cornua, or interferes with its destruction. In all of the work that has been reported in the attempt to establish histamine as the primary evocator in the decidual cell response and implantation, the blastocyst has been ignored. There has been no attempt to examine the living blastocyst itself and to determine the effects of the various drugs used on it. Con
sequently, the conclusions drawn as to the
failure of implantation are equivocal because
the condition of the implanting agent in the
experiment has not been evaluated. Also relevant is the fact mentioned earlier that the
decidual response in the rat and mouse is
evoked, not only by living embryos, but also
by many inert objects inducing the response
without evidence of epithelial destruction.
The mechanism of histamine release under
these conditions must be based on some unknown factor.
The appearance of implantation cones, just before and durine attachment of the blastocyst to the endometrium in guinea pigs, rabbits, squirrels, chipmunks, and probably primates, raises the question as to whether the embryo may not initially send protoplasmic extensions between the epithelial cells lining the lumen and thus secrete some substance which not only initiates the decidual response, but also effects the removal of underlying endometrial tissue (compare Figs. 14.23, 14.24 and 14.25) (Mossman, 1937; Wislocki and Streeter, 1938; Boving, 1954, 1959a j. It is interesting that during this initial invasion in the guinea pig, rabbit, and man, there is a negligible amount of endometrial necrosis. In the description of the implantation stages of the macaque, Wislocki and Streeter also emphasized that during the earliest
INNER CELL MASS
Fig. 14 23. Section of a ciuili.'a pig lila.-lo.-yst
showing the \eiy earliest stage in the attachment
of the abembiyonal pole cells to the maternal
endometrium. X 500.
864
Fig. 14.24. The (•.-Illy M.-itic of attacliiucnt of the O-day maca.iuc M im.hxm The .Miihryonic
pole is directed towards the uterine epithelium (Wislocki and Streeter, 1938).
Fig. 14.25. A section through an implanting rabbit blastocyst showing an unusually narrow
trophoblast invasion of the uterine epithelium. There is no evidence of epithelial debris
within the trophoblast cells. A group of clumped uterine epithelial nuclei surrounded by pale
cytoplasm lies to the left of the invading foot (Boving, 1959a). Fixation: Sousa, Azan stain.
X600.
phases of embryonic attachment to the uterine epithelium, the subepithelial mucosa shows no reaction whatever. When joined, these observations remind us that as yet there is no conclusive evidence that the implanting embryo secretes cytolytic enzymes but may secrete other substances.
The most imaginative experimental approach to the problems of embryo spacing, attachment, and implantation is the work of Boving (1959a, b and c, 1961) on the rabbit. He has clearly shown that, in this animal, invasion is promoted by a chemical substance elaborated witliin the blastocyst and transferred to the maternal circulation. The invasion-promoting substance has been characterized as being in the form of bicarbonate which induces a localized high 1)H. Circulating progesterone increases the level of endometrial carbonic anhydrase and accelerates the removal of bicarbonate from the embryo by catalyzing the formation of carbonic acid. The carbonic acid is converted to carbon dioxide which is removed by the maternal circulation. The local pH rises and the various blastocysts' membranes become very sticky, particularly at the site of attachment. The physicochemical interrelationship of the trophoblast and endometrial epithelium effects a dissociation of the epithelium, thus opening a path for the trophoblast.
At this writing, the precise roles of the egg and endometrium during implantaton are unknown and remain a challenging problem. The numerous modifications of the implantation processes in the different mammalian families create difficulties of interpretation in what is already an unusually complex problem. As more detailed descriptions of the embryo-endometrial relationships appear, it seems clear that neither the ovum nor the endometrium is primarily responsible for implantation, but that both play mutual and overlapping roles. One of the greatest gaps in our knowledge of implantation for any animal is a detailed description of the process itself and the precise timing of the events in this phenomenon. The various experimental approaches to the physiologic and biochemical mechanisms of implantation have quickened our interest and broadened our view of the complex metabolic processes required if implantation is to be successful, but our efforts to interpret correctly the data from biochemical, physiologic, and pharmacologic investigations will be limited until more accurate information has been obtained bearing on the morphologic features of the process itself.
V. References
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Alden, R. H. 1942a. The periovarial sac in the albino rat. Anat. Rec, 83, 421-434.
Alden, R. H. 1942b. The oviduct and egg transport in the albino rat. Anat. Rec, 84, 137-169.
Alden, R. H. 1942c. Aspects of the egg-ovaryoviduet relationship in the albino rat. I. Egg passage and development following ovariectomy. J. Exper. ZooL, 90, 159-169.
Alden, R. H. 1942d. Aspects of the egg-ovaryoviduct relationship in the albino rat. II. Egg development within the oviduct. J. Exper. Zool., 90, 171-181.
Alden, R. H. 1945. Implantation of the rat egg.
I. Experimental alteration of uterine polarity. J. Exper. Zool., 100, 229-235.
Alden, R. H. 1947. Implantation of the rat egg.
II. Alteration in osmiophihc epithelial lipids of the rat uterus under normal and experimental conditions. Anat. Rec, 97, 1-19.
Alden, R. H. 1948. Implantation of the rat egg.
III. Origin and development of primary trophoblast giant cells. Am. J. Anat., 83, 143-182.
Alfert, M. 1950. A cytochemical study of oogenesis and cleavage in the mouse. J. Cell. & Comp. Physiol., 36, 381-409.
Allen, B. M. 1911. The origin of the sex-cells of Amia and Lepidosteus. J. Morphol., 22, 1-36.
Allen, E. 1922. The oestrus cycle in the mouse. Am. J. Anat., 30, 297-371.
Allen, E. 1923. Ovogenesis during sexual maturity. Am. J. Anat., 31, 439^81.
Allen, E., Pratt, J. P., Newell, Q. U., and Bland, L. J. 1930. Human tubal ova; related early corpora lutea and uterine tubes. Contr. Embryol , Carnegie Inst. Washington, 22, 45-76.
Allen, W. M. 1931. I. Cyclic alterations of the endometrium of the rat during the normal cycle, pseudopregnancy, and pregnancy. II. Production of deciduomata during pregnancy. Anat. Rec, 48, 65-103.
Allen, W. M., and Corner, G. W. 1929. Physiology of the corpus luteum. III. Normal growth and implantation of embryos after very early ablation of the ovaries, under the influence of the corpus luteum. Am. J. Physiol., 88, 340-346.
Amoroso, E. C, Griffiths, W. F. B., and Hamilton, W. J. 1942. The early development of the goat (Copra hirciis). J. Anat., 76, 377-406.
Amoroso, E. C, and P.\rkes, A. S. 1947. Effects on embryonic development of x-irradiation of
866
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Reference: Young WC. Sex and internal secretions. (1961) 3rd Eda. Williams and Wilkins. Baltimore.
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