Estradiol regulation of the secretory immune system in the female reproductive tract: IgA in uterine and vaginal secretions of rats following portacaval anastomosis

The uterine immune system is under the control of estradiol which acts to increase the levels of both IgA and secretory component (SC) in uterine secretions. The objective of the present study was to determine whether serum is the primary source of the IgA which enters uterine secretions in response to estradiol. To examine this, serum IgA levels in rats were surgically elevated by portacaval anastomosis which prevents hepatic clearance of IgA. Under these conditions, IgA levels in serum were 2- to 4-fold higher than those of intact or sham-operated animals. Levels of IgA in uterine secretions of portacaval animals, however, were significantly lower than those measured in controls when animals were ovariectomized and treated with estradiol. IgA in vaginal secretions of portacaval animals was greater than that in sham-operated or intact rats. To determine whether IgA had leaked from the uterus into vaginal secretions, a second group of animals had their uteri ligated at the utero-cervical junction prior to hormone treatment. Following estradiol stimulation, uterine IgA levels in portacaval animals were the same as those measured in intact and sham-operated animals. When free SC was measured in uterine secretions of ligated rats, levels were the same in all three groups. These studies indicate that elevated levels of serum IgA did not lead to a rise in uterine IgA. Further, since SC, which is thought to be a receptor for transporting IgA into mucosal secretions, remained unchanged, it appears unlikely that IgA movement into the uterine lumen was transport limited. These studies suggest that the presence of IgA in uterine and vaginal secretions is not due exclusively to serum contributions but may involve local synthesis of IgA.     

Glucocorticoid regulation of the humoral immune system. I. In vivo effects of dexamethasone on IgA and IgG in serum and at mucosal surfaces

The present studies were undertaken to determine whether glucocorticoids influence the levels of Ig in serum, saliva, and vaginal secretions. When measured by RIA, IgA levels in serum were elevated when increasing doses of dexamethasone, a potent synthetic glucocorticoid, were administered to intact- and adrenalectomized-ovariectomized rats. In contrast, IgA levels decreased in saliva and vaginal secretions over the same dose range. Time course studies indicated that the decline in salivary IgA, observed at 24 h after a single injection of dexamethasone, preceded a rise in serum IgA detected at 24 h after the second hormone treatment. Both responses were maximal at day 2 and did not change with further hormone exposure. After immunization and boosting with SRBC at two mucosal sites (intestinal Peyer's patch and uterine lumen), dexamethasone increased anti-SRBC IgA antibody levels in serum and reduced their presence in vaginal secretions. In contrast, anti-SRBC IgG-antibody levels in serum and vaginal secretions were reduced with hormone treatment. In the absence of hormone treatment, pooled sera from nonimmunized animals, when analyzed by HPLC, contained polymeric and dimeric IgA that was present in roughly equal proportion. In response to dexamethasone, polymeric IgA increased to a greater extent than did monomeric IgA. In summary, these studies demonstrate that dexamethasone alters the levels of IgA as well as specifically directed IgA and IgG antibodies in secretions and serum. Further, it suggests that glucocorticoid controlled IgA increases in serum and decreases in vaginal and salivary secretions may be due, in part, to a redistribution of polymeric IgA from mucosal surfaces to serum.     

In vivo response of secretory component in the rat uterus to antigen, IFN-gamma, and estradiol

Intrauterine immunization of ovariectomized rats with SRBC is known to elicit pronounced IgA and IgG antibody responses in uterine secretions of immunized uteri. To determine whether secretory component (SC), the receptor for transporting polymeric IgA from tissues to mucosal surfaces, was also influenced by Ag, ovariectomized rats were immunized and boosted by placing SRBC into the lumena of individual uterine horns. In response to Ag, the levels of polymeric IgA, as well as free SC and SC bound to polymeric IgA, increased in uterine secretions. When ovariectomized animals were treated with estradiol, a fivefold increase in SC levels was observed in the immunized horns, indicating that a hormone response is superimposed on the Ag-induced stimulation of uterine SC. To determine whether IFN-gamma influences the presence of SC in uterine secretions, IFN-gamma was placed in the uterine lumena of ovariectomized nonimmunized rats. When uterine secretions were analyzed, significantly higher levels of SC were found in IFN-gamma-exposed uteri than were present in saline treated control animals. In contrast, intrauterine instillation of IFN-gamma had no effect on the levels of IgA in uterine secretions. This response was specific for IFN-gamma in that IFN-alpha/beta had no effect on uterine SC or IgA levels. These results indicate that intrauterine instillation of Ag, in addition to evoking pronounced antibody responses, stimulates the production of SC, which may be responsible for the transport of polymeric IgA from tissue to uterine secretions. Furthermore, they indicate that IFN-gamma placed in the uterine lumen stimulates SC production and suggest that the uterine SC response to Ag may be mediated by the action of IFN-gamma on uterine epithelial cells.     

Slight influence of the estrous cycle stage on the mucosal and systemic specific antibody response induced after vaginal and intraperitoneal immunization with protoxin Cry1Ac from Bacillus thuringiensis in mice

Since the immune response appears to be variable according to the hormonal stage of the mammalian female, the aim of this study was to determine whether estrous cycle stage modifies the mucosal and systemic immune responses induced by intraperitoneal and vaginal immunization of mice with protoxin Cry1Ac. We tested the influence of three immunizations on the specific antibody response elicited at estrus and diestrus, that were the same estrous cycle stages at which the antigen was applied. Both intraperitoneal and vaginal immunization of mice with Cry1Ac either at estrus or diestrus induces specific antibody responses at serum, vagina and large intestine. The stage of the estrous cycle have little or non influence in the magnitude of the response induced, since only at serum the IgM was slightly higher at estrus than at diestrus by both routes. At the large intestine only the IgA response elicited via the intraperitoneal route changed, being higher at diestrus, whereas at the vagina IgA response induced did not change significantly due to the cycle stage. Present results suggest that Cry1Ac may be used as an antigen carrier as it can elicit antibody responses at systemic level and at several mucosal sites including the vagina that are not modified significantly throughout the reproductive cycle.     

Progesterone regulation of secretory component (SC): uterine SC response in organ culture following in vivo hormone treatment

Sex steroid hormones are known to have profound effects on mucosal immunity. In the present study we evaluated the effects of progesterone on the uterine immune system by determining the changes in the levels of secretory component (SC) released from uterine tissues in culture following in vivo administration of progesterone to estradiol-stimulated ovariectomized rats. SC is a transport protein which moves IgA into external secretions such as intestinal and uterine secretions. SC release was determined by radioimmunoassay of the culture medium collected 24 h after introduction of uterine tissues into medium with or without cycloheximide. The net production of SC was reduced following progesterone administration. Reduction in SC levels followed a dose dependency and occurred irrespective of whether the progesterone was given before or during treatment with estradiol. These results support the hypothesis that progesterone plays a direct role in suppression of uterine SC production and release.     

Estradiol and progesterone regulation of immunoglobulin A and G and secretory component in cervicovaginal secretions of the rat

The present study examined the influence of hormones on the levels of immunoglobulins A (IgA) and G (IgG) and secretory component (SC) in cervicovaginal secretions of ovariectomized rats. Administration of estradiol to ovariectomized rats resulted in a significant decline in cervicovaginal content of IgA, IgG and SC. This response was dose dependent and was not prevented by administration of dexamethasone, a potent synthetic glucocorticoid, with estradiol. Treatment of ovariectomized rats with progesterone also lowered the levels of IgA and SC in cervicovaginal secretions. In contrast, dexamethasone had no apparent vaginal effect. The action of estradiol on cervicovaginal IgA, IgG and SC appears to be independent of uterine influence. This conclusion is based upon our observation that estrogen treatment of rats with ligations at their uterocervical junction still have decreased cervicovaginal IgA and SC levels. In parallel with this inhibitory effect, estradiol administration stimulated the accumulation of IgA and SC in uterine secretions. These findings indicate that the sex hormones play a role in regulating IgA, IgG and SC content in cervicovaginal secretions. In addition, it suggests that hormonal balance in females may influence the immune response of the reproductive tract to infectious disease.     

A study of prostaglandin F2alpha as the lutbolysin in swine: IV An explanation for the luteotrophic effect of estradiol

This study evaluated effects of estradiol valerate on synthesis, secretion and direction of movement of immunoreactive prostaglandin F2alpha (PGF) in swine. Gilts were randomly assigned to provide uterine flushings representing days 11, 13, 15, 17 and 19 of the estrous cycle (three gilts/day). The same gilts then were allowed one estrous cycle for recovery. During the second postoperative estrous cycle they were treated with estradiol valerate (EV) (5mg/day, SC) on days 11 through 15 and uterine flushings again were obtained on the same respective days with the same gilts represented within each day. Total recoverable PGF per uterine horn increased from day 11 (X - 1.98 ng) to day 17 (X = 210.20 ng) and then declined to day 19 (X = 66.20 ng) during the control period. Following EV treatment average total recoverable PGF was the control period. Following EV treatment average total recoverable PGF was 1.9, 4,144.3 and 4,646.7 ng on the same respective days. EV treatment also resulted in maintenance of elevated levels of total protein and acid phosphatase activity in uterine flushings. These data suggest that estradiol may exert its luteotrophic effect by preventing the release of PGF from the uterine endometrium into the uterine venous system (endocrine secretion) while maintaining the movement of endometrial secretions into the uterine lumen (exocrine secretion).     

A study of prostaglandin F2α as the luteolysin in swine: IV an explanation for the luteotrophic effect of estradiol

This study evaluated effects of estradiol valerate on synthesis, secretion and direction of movement of immunoreactive prostaglandin F_2α (PGF) in swine. Gilts were randomly assigned to provide uterine flushings representing days 11, 13, 15, 17 and 19 of the estrous cycle (three gilts/day). The same gilts then were allowed one estrous cycle for recovery. During the second postoperative estrous cycle they were treated with estradiol valerate (EV) (5mg/day, SC) on days 11 through 15 and uterine flushings again were obtained on the same respective days with the same gilts represented within each day. Total recoverable PGF per uterine horn increased from day 11 (¯X = 1.98 ng) to day 17 (¯X = 210.20 ng) and then declined to day 19 (¯X = 66.20 ng) during the control period. Following EV treatment average total recoverable PGF was 1.9, 4,144.3 and 4,646.7 ng on the same respective days. EV treatment also resulted in maintenance of elevated levels of total protein and acid phosphatase activity in uterine flushings. These data suggest that estradiol may exert its luteotrophic effect by preventing the release of PGF from the uterine endometrium into the uterine venous system (endocrine secretion) while maintaining the movement of endometrial secretions into the uterine lumen (exocrine secretion).     

Shifts in gonadotropin and steroid levels that precede anestrus in female golden hamsters exposed to a short photoperiod

Female golden hamsters exposed to short photoperiods become anestrous and exhibit daily surges of gonadotropins and progesterone. Since little is known about the transition between the cycling and anovulatory states, the following experiments were done to determine whether there are hormonal changes that precede cessation of estrous cyclicity. Females killed on the morning of estrus, up to the tenth estrous cycle in short days, showed no hormonal or ovarian morphologic evidence of changes in reproductive function. When assessed on the afternoon of estrus, however, serum levels of luteinizing hormone and progesterone increased significantly before vaginal and ovarian cyclicity ceased. Females sampled in both the morning and afternoon at increasing durations since their last vaginal estrus revealed that maximal daily surges of both gonadotropins and progesterone were not consistently manifested until the vaginal cycle had been absent for 2 weeks. By then, estrogen levels and uterine weights were low and ovaries showed hypertrophied interstitia and arrested follicular growth. We have demonstrated that there are hormonal changes in females before the loss of the vaginal cycle and onset of major daily hormonal surges. Our results suggest that alterations in feedback relationships between steroid hormones and gonadotropins may precede photoperiod-induced anestrus.     

Levels of prostaglandin F (PGF) in bovine endometrium uterine venous, ovarian arterial and jugular plasma during the estrous cycle (38789).

Prostaglandins F (PGF) were measured in uterine vein, ovarian artery, and jugular vein plasma and in the endometrial tissues at various times during the bovine estrous cycle, and were compared to peripheral plasma progesterone levels. Four groups of heifers at days 1-5, 10-14, 15-17 and 20-0 of the estrous cycle were studied. Low levels of PGF (48 plus or minus 12 ng/g dry tissue were measured in the endometrium on days 1-14 of the cycle. Higher values (131 plus or minus 9.0) were found at days 15 until the day of estrus (p less than 0.001). Similarly, very low levels of PGF were observed in the uterine vein plasma at days 1-14 (0.162) plus or minus 0.044) ng/mlM plus or minus S.E.), whereas on days 15 until the day of estrus the levels ranged from 1.5 to 3.0 ng/ml. The increases in uterine vein PGF on day 15 occurred even while peripheral plasma progesterone levels were still high. However, PGF was not elevated in either the ovarian artery or the jugular vein at any time during the cycle, even when uterine vein levels were greatly elevated. No differences in PGF content were detected in endometrial tissue from uterine horns adjacent or opposite to the functional corpus luteum.     

Disruption of the tissue inhibitor of metalloproteinase-1 gene results in altered reproductive cyclicity and uterine morphology in reproductive-age female mice

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a multifunctional protein expressed in the uterus of essentially all species, yet the function of this protein is uncertain. To assess the role of TIMP-1 in the uterine events that occur during the murine estrous cycle, mature female TIMP-1 wild-type and null mice were monitored for reproductive cyclicity. Mice were sacrificed in each stage of the estrous cycle, and peripheral blood was collected and assayed for serum estradiol and progesterone content by RIA. Uterine morphology and TIMP-1, TIMP-2, TIMP-3, and TIMP-4 mRNA expression were also examined between genotypes in each stage of the estrous cycle. Disruption of the TIMP-1 gene product was associated with an altered reproductive cycle characterized by a significant decrease in the length of the estrus period in the null mice. Also during the period of estrus, null mice expressed significantly lower levels of uterine TIMP-3 mRNA expression, altered uterine morphology, significantly higher serum estradiol levels, and significantly lower serum progesterone levels compared to their wild-type counterparts. It is concluded from this study that TIMP-1 has a multifaceted role in regulating the murine reproductive cycle, and this control appears to be at the level of both the uterus and the ovary.     

GRP78 expression and immunohistochemical localization in the female reproductive tract of mice

The 78-kDa glucose-regulated protein (GRP78) is an endoplasmic reticulum chaperone, with multiple functional roles in protein processing and provision of cellular protection. However, the physiological role of GRP78 in embryo development is not clear. Localization of GRP78 and expression of its mRNA in the reproductive organs throughout the estrous cycle in mice were investigated by immunohistochemistry and real-time polymerase chain reaction, respectively. Whereas there was intense staining for GRP78 in the oviduct at estrus, the ciliated cells of isthmus had better staining than those of infundibulum and ampulla at all phases of the cycle. Furthermore, GRP78 was located in the uterine luminal and glandular epithelial cells throughout the estrous cycle, particularly during the estrus phase. However, levels of GRP78 mRNA in the oviduct and uterus varied during the cycle, with peaks at estrus. In conclusion, GRP78 expression varied with the phase of the murine estrous cycle; this might be related to gamete transport, fertilization and early development of the zygote/embryo.     

Fluctuations of lactoferrin protein and messenger ribonucleic acid in the reproductive tract of the mouse during the estrous cycle.

The physiological role of lactoferrin (LF), the major estrogen-inducible protein in the murine uterus, is unclear; however, LF may be a useful marker for the study of estrogen action in the uterus. Thus, the expression of LF mRNA and the localization of the protein in genital tract tissues and secretions of female mice (6-8 wk old) at different stages of the estrous cycle were investigated. Uterine luminal fluid (ULF) was analyzed for LF by means of gel electrophoresis and Western blot techniques; LF mRNA and protein were identified in reproductive tract tissues through in situ hybridization and immunocytochemistry. At diestrus, the level of LF mRNA was low, and staining for the protein was very light in uterine epithelial cells; LF was undetectable in ULF. At proestrus, LF mRNA and protein increased in the uterine epithelium and LF was readily detectable in ULF. LF mRNA and protein reached the highest levels at estrus. At early metestrus as compared to estrus, LF mRNA and protein were detected in decreasing amounts in uterine epithelial cells; the protein was undetected in ULF. By late metestrus and diestrus, LF mRNA and protein returned to a low level, and the protein was undetectable in ULF. LF protein was also demonstrated by immunocytochemistry in the epithelium of the oviduct, cervix, and vagina. LF protein fluctuation similar to that observed in the uterus was seen in these tissues; however, the uterus demonstrated the most dramatic changes in the number of epithelial cells involved in LF production during the estrous cycle. In summary, LF mRNA and its expression in uterine epithelial cells of the mouse varied with the stage of the estrous cycle. These results, combined with previously reported findings that LF is a major constituent of mouse ULF under the influence of estrogen, suggest that LF may play an important role in normal reproductive processes.     

Changes in the distribution of ZO-1, occludin,and claudins in the rat uterine epithelium during the estrous cycle

During the estrous cycle, the endometrium epithelium experiences marked cellular structural changes. For fertilization to proceed, maintenance of an adequate uterine environment by ovarian hormones is essential. Epithelial cells lining the uterine lumen are associated with each other by tight junctions (TJs), which regulate the passage of ions and molecules through the paracellular pathway. The aim of the present study was to assess by confocal immunofluorescence the distribution pattern of the TJ proteins ZO-1, occludin, and claudins 1–7 in the rat uterus during the estrous cycle. Our results reveal that on proestrus, the day when mating takes place, ZO-1, occludin, and claudins 1 and 5 are located in the TJs, while claudins 3 and 7 display a basolateral distribution. In contrast, on metestrus day, when no sexual mating occurs and the uterine lumen is devoid of secretions, none of these proteins were detected in the TJ region, and only a diffuse cytosolic staining was observed for some of the proteins. On estrus and diestrus days, an intermediate situation was encountered, since ZO-1 localized in the TJs, whereas occludin was no longer detectable in the TJs. The distribution of claudins during these stages varied from the lowermost portion of the basolateral membrane to its apex. In conclusion, the results show that the protein composition of TJs present in the luminal epithelial cells of the uterus changes during the different days of the estrous cycle, and suggest that the expression of TJ proteins participates in providing an adequate environment for a successful fertilization.This work was supported by grants PAPIIT (IN210902, IX228504) and PAIP (6190-08) from the National Autonomous University of Mexico (UNAM), and by grants G34511-M and 37846-N from the Mexican National Council on Science and Technology (CONACYT).     

Estrous changes in vaginal nociception in a rat model of endometriosis

A rat model of endometriosis, in which pieces of uterine horn (versus fat in controls) are autotransplanted into the abdomen where they form cysts, reduces fecundity and produces vaginal hyperalgesia. The cysts gradually enlarge over a 2-month period postsurgically and then plateau. Cysts regress with low estrogen levels and reappear when they rise. Based on the hypothesis that the vaginal hyperalgesia depends upon the cysts, this study tested two predictions: that (1) the hyperalgesia would develop postsurgically in parallel with the cysts, and (2) the hyperalgesia would vary with estrous, being greatest when estrogen levels are high (proestrus) and least when low (estrus). In rats trained to escape vaginal distention, percentage escape responses to different distention volumes were measured across the rat's 4-day estrous cycle for 2.5 months before and up to 4 months after autotransplantation of uterus (n=9) or fat (n=6) in abdominal sites. Vaginal pressures were also measured. In rats with uterine but not fat autotransplants, escape percentages increased postsurgically over a 2-month period and then plateaued. The increase was greatest in proestrus and failed to occur in estrus. Vaginal pressures were unchanged in all groups. These results strongly support the hypothesis that the vaginal hyperalgesia depends upon the cysts. Because the cysts were located in sites remote from the vagina, the hyperalgesia involves viscero-visceral interactions and is likely centrally mediated, whereas the estrous modulation could involve hormonal actions either on the cysts or, more likely, on vaginal afferent fibers, and/or on central neurons.     

Detection of bradykinin and bradykinin-beta(2) receptors in the porcine endometrium during the estrous cycle and early pregnancy

During the period of attachment of the trophectoderm to the uterine lumenal surface in the pig, there is an increase in uterine blood flow and a localized hyperemic response induced by the developing conceptuses. The presence of tissue kallikrein in the porcine uterine lumen suggests that the kallikrein-kinin system may be functional during pregnancy in the pig. The objective of the present study was to determine the concentration of bradykinin within the uterine lumen during the estrous cycle and early pregnancy as well as endometrial gene expression and cellular localization of the bradykinin beta(2) receptor. Concentration of bradykinin in uterine flushings was greatest during estrus (Day 0) and Days 12-18 of the estrous cycle. However, there was a 5- to 10-fold increase in bradykinin content in pregnant uterine flushings on Days 12-18 of pregnancy compared with the estrous cycle. Endometrial bradykinin beta(2) receptor gene expression was greatest on Days 0, 12, 15, and 18 of the estrous cycle and pregnancy as gene expression decreased almost 6-fold on Days 5 and 10. Bradykinin beta(2) receptors were detected in the endometrial surface and glandular epithelium with greatest intensity of staining observed on Days 0, 12, 15, and 18 of the estrous cycle and pregnancy. Results from the present study suggest that the kallikrein-kinin system plays a role in the establishment of pregnancy in the pig.     

Male hamsters discriminate estrous state from vaginal secretions and individuals from flank marks

It is clear that male hamsters discriminate between the odors of individual, conspecific females, as shown by using habituation-dishabituation methods. However, it is not clear from past research whether male hamsters are able to discriminate between the odors of estrous and non-estrous females. A series of habituation-dishabituation experiments was conducted to determine whether males discriminated between different estrous cycle states using two female secretions, those from flank-glands and vaginal secretions. We found that, when habituated to a female flank-gland secretion, males discriminated between this female and a second female on the test trial, whether both were in estrus, both were in diestrus, or one was in estrus and the other in diestrus. There was no difference, however, in the magnitude of their dishabituation response toward flank-gland odors of females in estrus and diestrus. These results suggest that males use flank-gland odors to gain information primarily about individuals. When tested with vaginal secretions in habituation-dishabituation tests, males only showed differences in investigation when the second female was in estrus, indicating that males use vaginal secretions to gain information primarily about reproductive state.     

Relationship between opposite changes of vaginal and vestibular impedance during estrous cycle in sows

Several bioimpedance techniques have been developed for noninvasive monitoring of reproductive events occurring in cyclic gilts and sows. Our objective was to compare the changes of vaginal and vestibular impedance during the porcine estrous cycle (experiment 1). In addition, we examined the causes of impedance variations in the vaginal vestibule during periestrus (experiment 2). The vaginal and vestibular impedance were measured with specially designed instruments. Sows were monitored for estrus via exposure to a sexually mature boar. The impedance in the vagina decreased gradually after weaning (P<0.01) reaching its nadir 2 days before estrus and increased during estrus to near maximum 2 days after estrus onset (P<0.01). The vaginal impedance during diestrus reached approximately the same level as on the weaning day. In contrast, the impedance in the vaginal vestibule increased gradually after weaning, then markedly during estrus (P<0.01) reaching its maximum 2 days after the onset of estrus followed by an abrupt decrease during early diestrus (P<0.01). The vestibular impedance after early diestrus reached almost the same level as before estrus. A significant negative correlation was found between the vaginal impedance in proestrus and vestibular impedance in periestrus. In experiment 2, interaction of the interval from weaning to estrus and parity significantly influenced the vestibular impedance in periestrus. The breed of sows did not affect the impedance in the vaginal vestibule through the whole experiment. From the present study we conclude that closely related inverse changes of the vaginal and vestibular impedance take place in pigs during the estrous cycle.     

Specific IgA and IgG antibodies in the secretions of the female reproductive tract: effects of immunization and estradiol on expression of this response in vivo

Uterine and vaginal secretions collected from intact adult female rats were analyzed to determine whether immunization at sites distal to the reproductive tract had any effect on the presence of specific IgA and IgG antibodies in genital tract secretions. Peyer's patch and i.p. immunization and boost with sheep red blood cells (SRBC) stimulated the appearance of specific IgA antibodies in uterine and vaginal secretions of uterine-ligated animals. IgG antibodies were also induced in uterine but not in vaginal secretions. In contrast, subcutaneous immunization and boost elicited a weak IgA uterine and IgG vaginal response. To establish the role of estradiol in regulating the presence of specific antibodies in the female genital tract, ovariectomized rats received primary and/or secondary Peyer's patch immunizations with hormone treatment. Administration of estradiol daily for 3 days before sacrifice resulted in a significant accumulation of IgA and IgG antibodies to SRBC in uterine secretions. In the absence of estradiol, antibody content was negligible. Vaginal antibody levels were also clearly influenced by estradiol. In contrast to the uterus, however, specific IgA and IgG antibodies were present in the vaginal secretions of saline-injected immunized animals and were markedly inhibited in animals treated with estradiol. These results indicate that antibodies in genital tract secretions can be induced by immunization of the Peyer's patches and that their presence in uterine secretions is clearly dependent on estradiol. Further, they indicate that gut-derived specific antibodies enter the vagina in the absence of hormone stimulation and that estradiol exerts an inhibitory effect on their presence in vaginal secretions.