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PubMed1987

Early embryonic development and preimplantation changes in the uterus of the bat Rhinopoma hardwickei hardwickei (Gray) (Rhinopomatidae).

Rhinopoma hardwickei hardwickei has an annual reproductive cycle. Although many of the females become inseminated from the latter half of February until about the middle of April, ovulation has not been recorded until the 11th of March. A single follicle reached full development and released one ovum from either of the ovaries with nearly equal frequency, and a single conceptus was carried in the ipsilateral uterine cornu during each cycle. The embryo descended into the uterus as an early morula and attained the bilaminar blastocyst stage before undergoing implantation. As the morula advanced in age, the embryonic surface of the zona became progressively more basophilic. Hence in advanced morulae, the inner surface of the zona pellucida took a dark stain with hematoxylin and appeared like a distinct thin membrane, while the rest of the thickness of the zona was eosinophilic. Although progestational changes commenced in both uterine cornua, they became augmented in the uterine cornu on the side of ovulation and blastocyst attachment. After blastocyst attachment, the contralateral cornu reverted to an anestrus condition. The progestational changes became less conspicuous from the cranial to the caudal end of the uterus. Evidently, there was a linear gradient in the progestational response of the uterus with the cranial end being most responsive and the caudal end least responsive. The precise mechanism which brings this about is not known.

Animals↗
PubMed1992

Adenosine levels in the postimplantation mouse uterus: quantitation by HPLC-fluorometric detection and spatiotemporal regulation by 5'-nucleotidase and adenosine deaminase.

Extracellular adenosine has the potential to influence many aspects of target cell metabolism. The present study has determined the endogenous levels of adenosine in the pregnant mouse uterus and developing embryo-decidual unit with respect to the expression of two key enzymes of adenosine metabolism, 5'-nucleotidase (5'-NT; EC 3.1.3.5) and adenosine deaminase (ADA; EC 3.5.4.4). To measure adenosine levels, nucleoside extracts were etheno-derivatized and quantitated by high-performance liquid chromatography-fluorescence detection (0.03 pmol/mg protein sensitivity). Adenosine levels were determined to be 0.18 nmol/mg protein in the nonpregnant uterus; however, two statistically significant changes were identified in the pregnant uterus: (1) a periimplantation surge between day 3 (0.24 nmol/mg protein) and day 5 (0.59 nmol/mg protein) of gestation (plug day 0; implantation day 4); and (2) an early postimplantation decline between day 6 (0.54 nmol/mg protein) and day 7 (0.10 nmol/mg protein). The periimplantation adenosine surge coincided with uterine expression of 5'-NT, an enzyme which catalyzes the irreversible dephosphorylation of 5'-AMP to adenosine. 5'-NT expression was shown by Northern blot analysis to peak in the embryo-decidual unit on day 5 of gestation and then to decline through day 9; transcripts remained elevated in the placenta between day 9 and day 13 (the latest day examined in this study). By use of specific enzyme histochemistry, most 5'-NT activity was localized to the primary decidual zone on day 5. This expression subsequently declined during regression of the primary decidua; however, 5'-NT appeared on giant trophoblast (days 7-13) and the metrial gland (days 11-13). Other purine catabolic enzymes degrading AMP (adenylate deaminase) or generating adenosine (S-adenosylhomocysteine hydrolase) were not detected in the embryo-decidual unit suggesting that the net flux of utero-placental AMP catabolism proceeds with adenosine as an intermediate, this being the major pathway of adenosine formation. The sharp drop in adenosine levels between day 6 and day 7 coincided with a rise in the activity and mRNA expression of ADA, an enzyme which catalyzes the irreversible deamination of adenosine to inosine. ADA was previously localized to the secondary decidual zone (days 6-11), secondary giant cells (days 7-13), and spongiotrophoblasts (days 8-13) in the mouse (Knudsen et al., 1991). Results of developmental Northern blot analysis demonstrated a direct correlation of relative 5'-NT/ADA mRNA band intensity to adenosine content between day 4 and day 9 of gestation, suggesting that the local availability of adenosine in the antimesometrium is dependent upon the distribution of these enzymatic activities.(ABSTRACT TRUNCATED AT 400 WORDS)

5'-Nucleotidase↗
PubMed1990

Central distribution of afferent pathways from the uterus of the cat.

Afferent pathways from the uterus of the cat were labeled by injections of horseradish peroxidase (HRP), wheat germ agglutinin-HRP, or fluorescent dyes into the uterine cervix and uterine horns. Afferent input to the uterus arises from small to medium size neurons (average size 31 x 28 microns) in dorsal root ganglia at many levels of the spinal cord (T12-S3). The segmental origin correlates with the location of the afferent terminal field in the uterus. Eighty-seven percent of the dorsal root ganglion cells (average, 822 on one side) innervating the cervix are located in sacral ganglia, whereas 97% of the cells innervating the uterine horn (average 479 on one side) are located in lumbar ganglia. Double dye labeling experiments indicate that a small percentage (average 15%) of lumbar neurons innervating the uterine cervix also innervate the uterine horn. The majority (70-80%) of afferent input to the uterine cervix passes through the pelvic nerve and the remainder through the pudendal nerve, whereas afferent input to the uterine horn must travel in sympathetic nerves. Ovariectomy (10-14 days) did not change significantly the number, sizes, or segmental distribution of uterine afferent neurons. In some cats (25%) injections of WGA-HRP into the uterine cervix labeled neurons (90-125 per animal) in lamina VII in the S2 spinal segment in the region of the sacral parasympathetic nucleus. Central projections of uterine horn afferent neurons were not labeled; however, afferent projections from the cervix were detected in the sacral spinal cord. The most prominent labeling was present in Lissauer's tract and in lamina I and outer lamina II on the lateral edge of the dorsal horn. From this region some labeled axons extended through lamina V into the dorsal gray commissure. Very few afferents were labeled on the medial side of the dorsal horn. These results are discussed in regard to the physiological function of uterine afferents and the possible transmitter role of vasoactive intestinal polypeptide, which is present in a large percentage (70%) of cervical afferent neurons.

Afferent Pathways↗
PubMedDate not supplied

Hysteroplasty and vaginoplasty for reconstruction of the uterus.

A simple surgical procedure for reconstruction of the uterus from available Müllerian bulbs with simultaneous vaginoplasty is described. The Müllerian bulbs on both sides are incised, and suitable central fibromuscular tissue is excised to make a uterine cavity. The margins are sutured around a uterine mold, taking care to leave tubal os free. The reconstructed lower end of the uterus (now representing the cervix and upper third of the vagina) is brought down into the space already made out of the peritoneal septum between the bladder and the rectoanal region. The perineal operation for vaginoplasty is completed after suturing the lower end of the reconstructed uterus to the upper margin of the reconstructed vagina. The vaginal and uterine molds are kept in place for one and two weeks postoperatively, respectively.

Female↗
PubMed2001

Subcellular distribution of native estrogen receptor alpha and beta isoforms in rabbit uterus and ovary.

The association of estrogen receptors with non-nuclear/cytoplasmic compartments in target tissues has been documented. However, limited information is available on the distribution of estrogen receptor isoforms, specially with regard to the newly described beta isotype. The subcellular localization of estrogen receptor alpha and beta isoforms was investigated in rabbit uterus and ovary. Native alpha and beta subtypes were immunodetected using specific antibodies after subjecting the tissue to fractionation by differential centrifugation. The ovary expressed alpha and beta estrogen receptors in predominant association to cytosolic components. However, in the uterus, a substantial proportion of the total estrogen binding capacity and coexpression of the two isoforms was detected in mitochondria and microsomes. The mitochondrial-enriched subfraction represented an important source of 17beta-estradiol binding, where the steroid was recognized in a stereospecific and high affinity manner. The existence of mitochondrial and membrane estrogen binding sites correlated with the presence of estrogen receptor alpha but mainly with estrogen receptor beta proteins. Using macromolecular 17beta-estradiol derivatives in Ligand Blot studies, we could confirm that both alpha and beta isoforms were expressed as the major estrogen binding proteins in the uterus, while estrogen receptor alpha was clearly the dominant isoform in the ovary. Other low molecular weight estrogen receptor alpha-like proteins were found to represent an independent subpopulation of uterine binding sites, expressed to a lesser extent. This differential cellular partitioning of estrogen receptor alpha and beta forms may contribute to the known diversity of 17beta-estradiol effects in target organs. Both estrogen receptor alpha and beta expression levels and cellular localization patterns among tissues, add complexity to the whole estrogen signaling system, in which membrane and mitochondrial events could also be implicated.

Animals↗
PubMed1995

Mouse uterus peptidylarginine deiminase is expressed in decidual cells during pregnancy.

Peptidylarginine deiminase is localized in the cytosol of the luminal and glandular epithelia of the nonpregnant murine uterus and its expression is regulated by sex hormones [Takahara et al., [1989]: J Biol Chem 264, 13361-13368; Takahara et al. [1992]: J Biol Chem 267,520-525]. Here, we demonstrate that changes occur in the enzyme level in the mouse uterus during pregnancy and parturition. After a rapid decrease in enzymatic activity from day 1 to day 5 of pregnancy, the activity sharply increased during the middle stage of pregnancy (day 8 to day 10) and then gradually decreased during late pregnancy. Expression of the enzyme occurred only in the decidual cells that had differentiated from endometrial stroma cells surrounding the implantation site. The immunochemical properties of the enzyme expressed in the decidualized cells was indistinguishable from those in the uterine epithelia. These results suggest that peptidylarginine deiminase has important roles in decidual cells and not just in the epithelia of the nonpregnant uterus. Moreover, the level of enzyme activity increased slightly just before parturition (day 17), and then decreased during the 12 h period after parturition. The tissue localization of the enzyme expressed around the time of parturition changed from decidua to the luminal and glandular epithelia. Semiquantitative analyses of the enzyme mRNA content in the pregnant uteri showed a remarkable increase from day 7 leading to the onset of the enzyme synthesis in the decidual cells. After reaching the maximal level at day 12, small peaks in the mRNA level were observed at two times during late pregnancy. Since these serial changes in the mRNA level did not correlate with changes in sex hormones, the expression of decidual peptidylarginine deiminase seemed to be controlled by factors other than sex hormones.

Animals↗
PubMed1991

Determination of the number and distribution of macrophages, lymphocytes, and granulocytes in the mouse uterus from mating through implantation.

The concentration and distribution of F4-80 positive cells (macrophages) and common leukocyte antigen (CLA) positive (bone marrow derived) cells were assessed in mouse uterus between days 1 and 8 of pregnancy. High numbers of polymorphonuclear leukocytes and lymphocytes were present on days 1 and 2, but not thereafter. Granulocytes were found both in the endometrium and within the luminal epithelium. The percentage of total cells contributed by macrophages was high on days 1 and 2. That percentage decreased significantly on day 3, then increased again on day 5 and remained high through day 8. Macrophages always were found in myometrial stroma. Macrophages were found throughout the endometrium on days 2 through 8. High numbers of macrophages were observed near epithelia, particularly on days 1, 2, 4, and 5. Few F4-80+ or CLA+ cells were observed within the developing primary and secondary decidua. The results demonstrate that an inflammation-like cellular response occurs in the uterus following mating and that macrophages are a major cellular component of the uterus during early pregnancy.

Animals↗
PubMed1993

Relationship between macrophage colony-stimulating factor production by uterine epithelial cells and accumulation and distribution of macrophages in the uterus of pregnant mice.

Estrogen and progesterone induce production of macrophage colony-stimulating factor (CSF-1) by uterine epithelial cells, and CSF-1 is produced in the uterus during pregnancy in mice. CSF-1 is a lineage-specific stimulator of macrophage proliferation, chemotaxis, and function. High concentrations of macrophages accumulate in the uterus during pregnancy. Experiments were conducted to determine whether a relationship exists between intrauterine CSF-1 production and the number and distribution of uterine macrophages during pregnancy in mice. The study demonstrated that on day 1 of pregnancy CSF-1 bioactivity levels were high. The number of macrophages in the uterus was also high on days 1 and 2, and macrophages were concentrated at epithelial surfaces. The decrease in CSF-1 bioactivity seen between days 1 and 2 was followed by a decrease in the macrophage concentration. An increase in CSF-1 bioactivity on day 4 was followed by an increase in the concentration of intrauterine macrophages. During the immediate postimplantation period, macrophages were detected primarily in the myometrium and deep endometrium and CSF-1 bioactivity was undetectable. During the second half of pregnancy, when CSF-1 concentrations were very high, the macrophage concentration was also very high and large numbers of macrophages were detected in association with epithelia. The data confirmed the existence of a direct relationship between intrauterine CSF-1 and macrophage accumulation and suggested that macrophages are attracted to epithelial surfaces by CSF-1.

Animals↗
PubMed1977

Progesterone retention by rat uterus I. Pharmacokinetics after uterine intraluminal instillation.

Tritium-labeled progesterone was administered to mature female rats in the proestrous stage by three different routes, gastric intubation, subcutaneous injection, and uterine intraluminal instillation, to study the kinetics involved in the uptake and retention of radioactivity by the uterus and various other tissues. Progesterone was retained at a much higher level and for a more prolonged period in the rat uterus after uterine intraluminal instillation. Progesterone bioavailability to the uterus was 45 times higher by uterine intraluminal instillation than by either gastric intubation or subcutaneous injection. Progesterone absorption by the rat endometrium was extremely fast. The observed biphasic decrease of radioactivity from the uterine tissue was explained adequately by a pharmacokinetic model in which progesterone is assumed to be present in two compartments within the uterine tissue. The pharmacokinetic parameters showed that the progesterone biological half-life in the uterine tissue during the alpha-phase was about 6.5 min while that in the beta-phase was about 230 min.

Animals↗
PubMed2002

Basigin expression and hormonal regulation in mouse uterus during the peri-implantation period.

Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, has been shown to be essential for fertilization and implantation. The aim of this study was to determine the expression and hormonal regulation of basigin gene in mouse uterus during the peri-implantation period. Basigin immunostaining and mRNA were strongly localized in luminal and glandular epithelium on day 1 of pregnancy and gradually decreased to a basal level from day 2-4 of pregnancy. Basigin mRNA expression in the sub-luminal stroma was first detected on day 3 of pregnancy and increased on day 4 of pregnancy. On day 5 of pregnancy, the expression of basigin protein and mRNA was only detected in the implanting embryos, and the luminal epithelium and sub-luminal stroma surrounding the embryos. A similar expression pattern of basigin was also induced in the delayed-implantation uterus which was activated by estrogen injection. On day 6-8 of pregnancy, although a basal level of basigin protein was detected in the secondary decidual zone, basigin mRNA expression was strongly seen in this location. Basigin mRNA was also highly expressed in the decidualized cells under artificial decidualization. Estrogen significantly stimulated basigin expression in the ovariectomized mouse uterus. A high level of basigin immunostaining and mRNA was also seen in proestrus and estrus uteri. These results suggest that basigin expression is closely related to mouse implantation and up-regulated by estrogen.

Animals↗
PubMed2001

Tissue inhibitor of matrix metalloproteinase-3 expression in the mouse uterus during implantation and artificially induced decidualization.

During implantation in mice, tissue inhibitor of matrix metalloproteinases-3 is believed to play a key role in inhibiting matrix metalloproteinase activity associated with embryo invasion and tissue remodeling. The first objective of this study was to quantitatively compare the steady-state mRNA levels of tissue inhibitors of matrix metalloproteinases between segments of the mouse uterus undergoing decidualization compared to those that are not during early pregnancy plus oil-induced decidualization. Steady-state tissue inhibitor of metalloproteinase-3 mRNA levels were significantly greater in implantation compared to interimplantation areas on days 6 and 7 of pregnancy and in stimulated compared to nonstimulated uterine horns at 48 and 72 hr after artificial induction of decidualization. Steady-state tissue inhibitor of metalloproteinase-1 mRNA levels were significantly greater in implantation compared to interimplantation areas on days 5-8 of pregnancy and in stimulated compared to nonstimulated uterine horns at 24, 48, and 72 hr after oil stimulation. Therefore, the steady-state mRNA levels of tissue inhibitors of metalloproteinase-1 and -3 increased in the uterus during decidualization. The second objective of this study was to determine if transforming growth factor-beta1 influences tissue inhibitors of metalloproteinase mRNA concentrations in mouse endometrial stromal cells. As determined by Northern blot analyses, transforming growth factor beta1 significantly increased tissue inhibitors of matrix metalloproteinases-1 and -3 mRNA levels in cultured mouse endometrial stromal cells isolated from uteri sensitized for decidualization. On the other hand, interleukin-1, epidermal growth factor, and leukemia inhibitory factor had no effect. The results of this study further characterize the tissue inhibitor of metalloproteinase expression in the uterus during implantation and artificially induced decidualization and the potential control of their expression in the stroma by transforming growth factor.

Animals↗
PubMed1990

Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus.

The multidrug resistance (mdr) gene family has been shown to encode a membrane glycoprotein, termed the P-glycoprotein, which functions as a drug efflux pump with broad substrate specificity. This multigene family is expressed in a tissue-specific fashion in a wide variety of normal and neoplastic tissues. The regulation of mdr gene expression in normal tissues is not understood. We have recently shown that mdr mRNA and the P-glycoprotein increases dramatically in the secretory luminal and glandular epithelium of the gravid murine uterus. This observation has suggested that mdr gene expression in the uterus is controlled by the physiologic changes associated with pregnancy. This report now demonstrates that mdr mRNA and P-glycoprotein are induced at high levels in the uterine secretory epithelium by the combination of estrogen and progesterone, the major steroid hormones of pregnancy. This regulation of mdr gene expression in the uterus does not require any other contribution from the fetus or placenta. The data indicate that this gene locus is hormonally responsive to estrogen and progesterone in the uterine secretory epithelium, suggesting an important and physiologically regulated role during pregnancy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Investigation of estrogen receptor alpha and beta mRNA expression in the pregnant rat uterus.

Although the expressions of the estrogen receptor (ER) subtypes have been demonstrated in a large number of estrogen target tissues, to date no evidence has been reported as to how the expressions of the alpha (alpha) and beta (beta) ER subtype mRNA alter in the rat uterus during pregnancy. The aims of the present study were to obtain information concerning the changes in the ER and the progesterone receptor (PR) in early pregnancy and to determine the alterations in the ER subtype mRNA in the pregnant rat uterus. To demonstrate the ER and PR densities, radioligand saturation assay was used. The reverse-transcription-polymerase chain reaction (RT-PCR) was applied to characterize the alterations in the ER subtype mRNA. ER expression was highest on day 5 of pregnancy (Bmax = 637.40 +/- 76.10 fmol/mg). The PR expression did not change significantly until day 8, but the protein density was increased on day 8 of pregnancy. The ERalpha mRNA expression was active during pregnancy, maximum expression was attained on day 5; a gradual decrease was then observed until the second half of pregnancy when its expression continuously increased up to the day of labor (day 22). Since the attachment of the blastocyst, an event that is dependent on estradiol in the progesterone-primed uterus of the rat, occurs on day 5 of pregnancy and the levels of the ER protein and the ERalpha mRNA on day 5 of pregnancy was the highest, it could be supposed that this subtype of ER might regulate implantation. The ERbeta mRNA was detected only from day 7 to day 15, with a maximum level on day 8. The expression of this ER subtype might be related to the development of decidual tissue.

Animals↗
PubMed2007

Regulation of MMP-9 expression and activity in the mouse uterus by estrogen.

Matrix metalloproteinases (MMPs) are spatiotemporally expressed in the uterus across normal estrous and menstrual cycles and are known to participate in the extensive endometrial tissue remodeling. MMP-9/gelatinase B is one of the major MMPs found in the uterus that modulates uterine biology during various reproductive processes. Although it seems that uterine MMP-9 is under ovarian steroid hormonal control, there are conflicting reports regarding steroidal hormonal regulation of MMP-9 expression, and there is little information on the effects of estrogen in vivo in this respect. We therefore examined the steroidal regulation of MMP-9 within the mouse uterus. Female mice (2-3 months old) were ovariectomized and treated with estradiol-l7beta (E(2)) or E(2) + progesterone (P(4)) and uterine gelatinase activity and expression were determined. Gelatin zymography revealed that E(2) alone or in combination with P(4) increased MMP-9 activation, whereas Northern analysis showed that E(2) decreased MMP-9 steady state mRNA expression and an estrogen receptor antagonist ICI-182, 780 blocked this effect. In contrast, uterine MMP-2 expression and activity were not affected by steroidal treatments. Pretreatment with a transcription inhibitor actinomycin D or translation inhibitor cycloheximide indicates that E(2) regulates uterine MMP-9 at multiple points, involving transcriptional and posttranscriptional control as well as modulation of inhibitor activities. Collectively, these data suggest that E(2) regulates uterine MMP-9 expression and activity in vivo via a complex mechanism. This estrogen regulation of MMP-9 activity may play an important role in uterine tissue remodeling.

Animals↗
PubMed1991

Oblique NMR imaging of the uterus in macaques: uterine response to estrogen stimulation.

We report methods for quantitative NMR imaging of the primate uterus and the application of these methods of measuring the response of the monkey (Macaca nemestrina) uterus (endometrial volume, myometrial volume, T2 values, myometrial junction zone) to estrogen stimulation. High-field (2.35 T), fat-suppressed, T2-weighted (TE50) oblique methods were used. Slice thickness, location, and angle were varied on each examination to obtain six contiguous slices between the cervix and fundus, regardless of size or orientation of the uterus. Basal endometrial and myometrial volumes were 0.05 +/- 0.01 cm3 and 1.31 +/- 0.23 cm3 in chronically ovariectomized animals. These increased by 15.7 +/- 3.6-fold and 3.1 +/- 0.4-fold, respectively, during 7 days of estrogen stimulation (estradiol benzoate, 5 micrograms/kg sc daily) while myometrial T2 increased from 52 +/- 1 to 67 +/- 4 ms. These changes reversed following menstrual bleeding.

Algorithms↗
PubMed1992

Quantitative MRI of the prostate and uterus in monkeys.

Quantitative MRI has been carried out in the prostate, seminal vesicles, uterus, and ovaries in the pig-tailed monkey, Macaca nemestrina. T2-weighted, fat-suppressed, multislice experiments were performed at 2.35 T. Eight males, 14 ovariectomized females, and 20 intact females were studied. In the prostate, the caudal and cranial lobe were readily distinguished since the latter had a longer T2 value. For all tissues and organs, interanimal variations were large (up to 12-fold variation in volume), but reproducibility was excellent in the prostate and in the ovariectomized monkey uterus with coefficients of variation (CV) of 3 and 5%, respectively. In the intact monkey uterus, cycle-cycle reproducibility was good with CVs of 6-10% in the myometrium and 14-18% in the endometrium. In the follicular phase, endometrial growth (+3.8% day-1, P < 0.001) was accompanied by myometrial shrinkage (-1.6% day-1, P < 0.001), while in the luteal phase, growth was seen in both tissues (+4.3% day-1, P < 0.001 and +1.4% day-1, P < 0.001, respectively). The great value of these MRI techniques in obtaining data in pharmacological efficacy studies of endocrine drugs, and in limiting the number of animals used, is discussed.

Animals↗
PubMed2002

Diabetes teratogenicity in mice is accompanied with distorted expression of TGF-beta2 in the uterus.

Early embryonic deaths as well as malformed newborns are among complications of the diabetic pregnancy. Cytokines and growth factors operating in the embryonic vicinity are found to be among factors that determine the sensitivity of embryos to external and internal detrimental stimuli, including diabetes. Transforming Growth Factor-beta2 (TGF-beta2) has been shown to be essential for embryonic development and survival. In the present work, we evaluated the pattern of TGF-beta2 expression in the uterus of streptozotocin-induced diabetic mice, demonstrating a decreased reproductive performance and elevated percentage of litters with severely malformed fetuses. Since stimulation of the maternal immune system was found to increase the resistance of mouse embryos to the teratogenic effect of diabetes, the effect of immunopotentiation on the expression of the cytokine was also investigated. TGF-beta2 expression was studied at the mRNA level by using the in situ hybridization technique and at the protein level by using the immunohistochemical analysis. A clear decrease in TGF-beta2 mRNA expression in the uterus of diabetic mice was observed at examined time points: days 1, 5, and 9 of pregnancy. Also, an evident reduction in TGF-beta2, the protein expression in the uterus of diabetic mice, was demonstrated at these time points. Maternal immunopotentiation that improved the reproductive performance of diabetic mice and reduced the number of the litters with malformed fetuses was also accompanied by a clear increase in the level of TGF-beta2 mRNA expression in the pregnant uteri. The above results clearly demonstrate that the embryotoxic effect of diabetes is accompanied by an alteration of TGF-beta2 expression. Immunopotentiation that was shown to improve the reproductive performance of the diabetic mice was accompanied by a partial normalization of TGF-beta2 expression in embryonic vicinity.

Animals↗
PubMed1998

Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in müllerian duct by the synthetic estrogen diethylstilbestrol (DES).

Mice deficient for the Abdominal B (AbdB) Hox gene Hoxa-10 exhibit reduced fertility due to defects in implantation. During the peri-implantation period Hoxa-10 is sequentially expressed in the uterine epithelium and stroma. These observations, combined with the stringent regulation of uterine implantation by ovarian steroids, prompted us to test whether estrogen and progesterone directly regulate the expression of Hoxa-10 and other AbdB Hoxa genes. Here we show that Hoxa-10 expression in the adult uterus is strongly activated by progesterone. This activation is blocked by the progesterone receptor antagonist RU486 and is independent of new protein synthesis. In addition, Hoxa-10 expression is repressed by estrogen in a protein synthesis-independent manner. Analysis of adjacent AbdB Hoxa genes reveals that Hoxa-9 and a-11 are also activated in a colinear fashion by progesterone but differentially regulated by estrogen. These results suggest that the regulation of AbdB Hox gene expression in the adult uterus by ovarian steroids is a property related to position within the cluster, mediated by the direct action of estrogen and progesterone receptors upon these genes. We next examined whether the embryonic expression of Hoxa10 is regulable by hormonal factors. Previous work has demonstrated that perinatal administration of the synthetic estrogen diethylstilbestrol (DES) to mice and humans produces uterine, cervical, and oviductal malformations. Certain of these phenotypes resemble those in Hoxa-10 knockout mice, suggesting that Hoxa-10 gene expression might be repressed by DES during reproductive tract morphogenesis. Exposure of the developing female reproductive tract to DES, either in vivo or in organ culture, represses the expression of Hoxa-10 in the Müllerian duct. Thus, these data not only establish a direct link between ovarian steroids and AbdB Hoxa gene expression in the adult uterus, but also provide a potential mechanism for the teratogenic effects of DES on the developing reproductive tract.

Animals↗