The relaxant property of local prostaglandin E2 on the non-pregnant uterus — A cyclic triphasic response

The response of the non-pregnant human uterus to intravenous(i.v.) injections and intra-uterine instillation of various doses of prostaglandin E₂ (PGE₂) was evaluated at the different phases of the menstrual cycle in 13 fertile regularly menstruating woemn who were neither lactating nor using any hormonal therapy. Uterine contractility was recorded by the microballoon technique in at least three sessions(proliferative, mid-cycle and secretory) in a single cycle with endometrial biopsy performed immediately following the last session to ascertain that the particular cycle was an ovulatory one. Single i.v. injections of PGE₂ had a consistent stimulatory effect on the contractility throughout the cycle with a tendency towards a decreased uterine response at mid-cycle and luteal phase as compared to the proliferative part of the cycle. Intra-uterine instilation of the compound induced a peculiar and interesting type of response. In the proliferative and secretory phases of the cycle the response was one of stimulation ; being more pronounced in the former period. However, around ovulation time, the local administration induced an evident uterine relaxation in most cases without any instance of stimulation. The possible implication of this triphasic response behaviour of the non-pregnant uterus within certain physiological events and pathological conditions is discussed.     

In vivo inhibition of the human non-pregnant uterus by prostaglandin E2

The discrepancy between the effect of PGE₂ on the non-pregnant myometrium (relaxation) as compared to (stimulation) has not yet been solved. Nine women in the early post-menopause volunteered for the investigation. Prostaglandin (PG) F_2α or E₂ was administered either by single intravenous (i.v.) injection or by intra-uterine instillation and the uterine contractility was recorded by the microballoon technique. The response of the menopausal uterus to i.v. injections of PGF_2α or PGE₂ was characterized by rapid stimulation while intra-uterine instillation of PGF_2α induced gradual but sustained elevation of uterine tonus. However, the intra-uterine injection of PGE₂ caused inhibition of different components of uterine contractility. The fact that PGE₂ can also inhibit the motility of the menopausal non-pregnant uterus coincides with earlier results i.e. the discrepancy may not exist. Moreover, in one cycling patient (13–18th days of the menstrual cycle) similar results were also obtained. Two theories were offered to explain why PGE₂ stimulated the uterus when given as a single i.v. injection but inhibited the same organ when instilled locally into the uterine cavity.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus in vivo.

The effect of locally administered prostaglandin E2 on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 mug PGE2 could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE2 was noted. An inhibition of uterine motility was observed during menstruation in response to 30--40 mug PGE2. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE2 which elicited increased or decreased uterine activity in this study. These findings suggest that PGE2 may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

Inhibitory effect of GnRH on isolated rat uterine muscle contractility

The effect of GnRH upon uterine contractions of both non-pregnant and pregnant rats was examined in vitro. In the non-pregnant rat uterus, GnRH inhibited in a concentration-and-time dependent manner the contractions induced by acetylcholine and oxytocin, but not those caused by bradykinin and angiotensin II. GnRH also inhibited the rhythmic contractions induced by oxytocin in uterine strips from late pregnant rats. These findings show that GnRH has a direct inhibitory effect on the rat uterine contractions, suggesting that GnRH-like substances may exert modulatory influences upon rat uterine contractility.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus in vivo

The effect of locally administered prostaglandin E₂ on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 μg PGE₂ could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE₂ was noted. An inhibition of uterine motility was observed during menstruation in response to 30–40 μg PGE₂. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE₂ which elicited increased or decreased uterine activity in this study. These findings suggest that PGE₂ may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

Menstrual cycle-associated alteration of sulfogalactosylceramide in human uterine endometrium: possible induction of glycolipid sulfation by sex steroid hormones

The human uterine endometrium is a tissue in which cell proliferation and differentiation are strictly controlled by sex steroid hormones, and these hormone-controlled cellular events occurring in association with the menstrual cycle of the uterine endometrium should be accompanied by characteristic molecular and metabolic changes. To characterize the menstrual cycle at the molecular level, we analyzed the glycolipids of human uterine endometrium in the proliferative and secretory phases of the menstrual cycle. Neutral glycosphingolipids from uterine endometrium comprised globo-series glycosphingolipids, such as GlcCer, LacCer, Gb3Cer, and Gb4Cer, and the relative concentrations remained constant in the two phases. However, in the case of acidic glycosphingolipids, although the concentrations of sialoglycosphingolipids remained at constant levels in the two phases, sulfatide, I3-SulfoGalCer, dramatically increased from the proliferative to the secretory phase, amounting to 7-17 nmol/g dry weight in the proliferative phase and 115-245 nmol/g dry weight in the secretory phase. Since sulfatide was the only glycolipid that changed in association with the menstrual cycle, it is likely that the sulfotransferase responsible for the synthesis of sulfatide might be induced by sex steroid hormones, estrogen and progesterone, and that sulfatide might play an essential biological role in the secretory phase of the menstrual cycle in the uterine endometrium.     

Secretory proteins in the reproductive tract of the snapping turtle, Chelhydra serpentina

SDS-polyacrylamide gel electrophoresis was used to separate the secretory proteins produced by the epithelial and endometrial glands of the uterine tube and uterus in the snapping turtle Chelydra serpentina. The proteins were analyzed throughout the phases of the reproductive cycle from May to August, including preovulatory, ovulatory, postovulatory or luteal, and vitellogenic phases. The pattern of secretory proteins is quite uniform along the length of the uterine tube, and the same is true of the uterus, but the patterns for uterine tube and uterus are clearly different. We identify 13 major proteins in C. serpentina egg albumen. Bands co-migrating with 11 of these are found in the uterine tube, but at most 4 are found in the uterus, suggesting that the majority of the albumen proteins are most likely secreted in the uterine tube, not in the uterus. Although some of the egg albumen proteins are present in the uterine tube only at the time of ovulation, most of the bands corresponding to albumen proteins are present throughout the breeding season even though the snapping turtle is a monoclutch species. These results suggest that the glandular secretory phase in the uterine tube is active and quite homogeneous in function regardless of location or phase of the reproductive cycle.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus in vivo

The effect of locally administered prostaglandin E₂ on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 μg PGE₂ could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE₂ was noted. An inhibition of uterine motility was observed during menstruation in response to 30–40 μg PGE₂. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE₂ which elicited increased or decreased uterine activity in this study. These findings suggest that PGE₂ may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus

The effect of locally administered prostaglandin E₂ on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 μg PGE₂ could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE₂ was noted. An inhibition of uterine motility was observed during menstruation in response to 30–40 μg PGE₂. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE₂ which elicited increased or decreased uterine activity in this study. These findings suggest that PGE₂ may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

正常妇女不同卵巢激素状态离体输卵管平滑肌自发收缩活动及其对NE反应性研究

通过离体实验方法观察58例22—40岁中国育龄正常妇女周期的不同阶段、妊娠期(1—2个月)及哺乳期(2—10个月)输卵管峡部平滑肌收缩频率、波型及对外源性去甲肾上腺素(NE)的反应。实验观察到增生期、行经期及哺乳期峡部收缩活动比分泌期、妊娠期强,前者收缩频率高,多数呈现阵发性收缩,而后者收缩频率低,呈现单个收缩。增生期、行经期、分泌期及哺乳期峡部对NE呈兴奋性反应,只有妊娠期峡部对NE呈抑制反应。峡部环层肌比纵层肌收缩力强,但收缩波型相似。结果表明人输卵管自发收缩活动及对NE反应与卵巢激素状态有密切关系。     

The effects of platelet-activating factor on the output of prostaglandins from the guinea-pig uterus

Platelet-activating factor (PAF) significantly increased the output of prostaglandin (PG) F2 alpha from the guinea-pig uterus during the mid-cycle phase (Days 6-10), but only had a small, non-significant stimulatory effect on the outputs of PGE2 and 6-keto-PGF1 alpha. PAF significantly increased the outputs of PGF2 alpha, PGE2 and 6-keto-PGF1 alpha from the guinea-pig uterus during the later phase of the cycle (Days 15-17). Lack of extracellular calcium did not affect the stimulatory effect of PAF on uterine PG output. However, TMB-8 (an intracellular calcium antagonist) prevented the increases in uterine PG output produced by PAF at both phases of the cycle. These results suggest that the stimulatory effect of PAF on uterine PG output in the guinea-pig is dependent upon the mobilization of intracellular calcium but is not dependent upon the uptake of extracellular calcium. Also, the weak stimulatory effect of PAF on PGE2 output from the uterus during the mid-cycle phase indicates that, if PAF is involved in implantation in guinea-pigs, it probably does not act via PGE2. Also, the lack of an inhibitory effect of PAF on uterine PGF2 alpha synthesis and release suggests that PAF is not the anti-luteolytic factor produced by the guinea-pig conceptus during early pregnancy.     

Regulation of cyclic guanosine monophosphate-dependent protein kinase in human uterine tissues during the menstrual cycle

Contractility of uterine smooth muscle is essential for the cyclic shedding of the endometrial lining and also for expulsion of the fetus during parturition. The nitric oxide (NO)-cGMP signaling pathway is involved in smooth muscle relaxation. The downstream target of this pathway essential for decreasing cytoplasmic calcium and muscle tone is the cGMP-dependent protein kinase (PKG). The present study was undertaken to localize expression of PKG in tissues of the female reproductive tract and to test the hypothesis that uterine smooth muscle PKG levels vary with the human menstrual cycle. Immunohistochemistry was used to localize PKG in myometrium, cervix, and endometrium obtained during proliferative and secretory phases. The PKG was localized to uterine and vascular smooth muscle cells in myometrium, stromal cells in endometrium, and a small percentage of cervical stromal cells. Using Western blot analysis and protein kinase activity assays, the expression of PKG was reduced significantly in progesterone-dominated uteri compared with myometrium from postmenopausal women or women in the proliferative phase. These findings support a role for PKG in the control of uterine and vascular smooth muscle contractility during the menstrual cycle.     

The effect of locally administered PGF2α on the contractility of the nonpregnant human uterus in vivo

The effect of locally administered prostaglandin F_2α on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied. An increase in uterine contractility in response to as little as 1.0 μg PGF_2α could be observed in all patients during both the early and late portions of the menstrual cycle, but at the time of ovulation a marked decrease in sensitivity was noted. Endogenous prostaglandin normally occurs in the secretory endometrium in levels compatible with the amount of exogenous prostaglandin which elicited increased uterine activity. These findings support the hypothesis that PGF_2α plays an important physiological role in the cyclical regulation of uterine motility during the human menstrual cycle.     

Coexpression and estrogen-mediated regulation of TRPV6 and PMCA1 in the human endometrium during the menstrual cycle

Maintenance of calcium balance in the uterus is essential for many of its functions, including embryo implantation. The plasma membrane Ca²⁺‐pumping ATPase proteins are encoded by four genes designated PMCA1‐4, and PMCA1 is expressed in the uterus of rats during the estrous cycle. Although transient receptor potential cation channel subfamily V, member 6 (TRPV6), has been detected in the human placenta, pancreas and the prostate gland, expression patterns of uterine TRPV6 and PMCA1 and their potential roles in the human endometrium remain to be elucidated. In the present study, the expression patterns of TRPV6 and PMCA1 were examined to predict their potential roles in the human endometrium during the menstrual cycle. Human classified endometrial tissues (total n = 40) were separated into three groups according to menstrual cycle phase: menstrual, proliferative (early‐, mid‐, late), and secretory phase (early‐, mid‐, late). The expression of TRPV6 and PMCA1 mRNA and protein in the uterine endometrium during the menstrual cycle increased by 1.5‐ to 1.8‐fold at the proliferative phase (early‐, mid‐, and late‐) in comparison to the other phases. Estrogen treatment caused a significant increase in TRPV6 and PMCA1 mRNA expression. Immunohistochemical analysis of the distribution of TRPV6 and PMCA1 in the uterus revealed that both proteins are abundantly expressed in the cytoplasm of endometrial and glandular epithelial cells during menstrual phases. Taken together, these results suggest that uterine expression of TRPV6 and PMCA1 may be involved in human reproductive function. Mol. Reprod. Dev. 78:274–282, 2011. © 2011 Wiley‐Liss, Inc.     

The use of catheter-tipped pressure transducers for chronic measurement of genital tract pressures in the ewe. II. Effects of oxytocin and prostaglandin F(2)alpha

Chronic catheterisation of the uterus, ampulla, and abdomen was performed in five ewes using solid-state, catheter-tipped pressure transducers. The catheters remained in place for up to 129 d, allowing in vivo studies of the effects of oxytocin and prostaglandin F(2)alpha (PGF(2)alpha). These agents did not produce any measurable increase in abdominal pressure. Intravenous (i.v.) oxytocin elicited a rapid increase in work done by both the uterus and ampulla. Intramuscular (i.m.) PGF(2)alpha produced a delayed uterine response but little change in the ampulla; i.v. PGF(2)alpha produced a rapid response at both sites. Low plasma progesterone concentrations (< 0.5 ng/ml) were associated with a greater uterine and ampullary response to oxytocin and with an enhanced uterine response to PGF(2)alpha. However, the uterine tube response to intravenous PGF(2)alpha was greatest when plasma progesterone concentrations were high.     

Absorption of prostaglandin E2 and uterine sensitivity of the non-pregnant and pregnant monkey in vivo

Radioactive (11-³H) prostaglandin E₂(PGE₂) levels in plasma of non-pregnant Rhesus and Japanese monkeys were determined by radioimmunoassay. The amounts of PGE₂ in plasma increased gradually and reached a peak 90 minutes after oral administration. Comparatively low levels were detected 24 hours after oral administration. Plasma PGE₂ levels increased rapidly and disappeared within 5 minutes when 5 μg/kg of PGE₂ was administered intravenously.Uterine contractile sensitivity to PGE₂ and F_2α was measured by the threshold of a venous dosage required to evoke an elevation of uterine contractility in non-pregnant and pre- and post-labor Japanese monkeys. Uterine sensitivity to PGE₂ in the non-pregnant monkey appear to vary in accordance with the sexual life span. At term of pregnancy, PGE₂ was much more potent in causing uterine contraction than PGF_2α. During labor and at postpartum period with lactation, effectiveness of PGE₂ appear to be less than that of PGF_2α. The non-pregnant and pregnant uterus of the third trimester are more sensitive to PGE₂ than the laboring and postpartum uterus.The long latency of the elevation of uterine contractility induced by the intravenous administration of PG suggests that the PG compounds have potent actions on the central nervous system.     

A comparison of uterine motility in the pregnant and non-pregnant cynomolgus monkey (Macaca fascicularis) and pregnant woman: a manometric and electromyographic study

The use of a combination of manometric and electromyographic methods provided a reliable technique for evaluating variations in uterine activity in conscious macaque monkeys and women. The technique was particularly useful for obtaining data on the influence of steroid hormones. During the spontaneous menstrual cycle of the macaque, uterine motility, after being weak and poorly synchronized during the follicular phase, became still weaker with impaired synchronization during the luteal phase and then much stronger and well-synchronized at the time of menstruation. There was no evidence in vivo of any relationship between the existence of gap junctions in the myometrium of non-pregnant animals and the various patterns of uterine motility. During the last third of pregnancy in macaques, the initiation of electrical activity in various uterine areas was always synchronous with and related to mechanical contraction. The same results were obtained in preparturient women. Thus, improved uterine coordination does not appear to be the mechanism by which the uterine contractile strength increases to expulse the foetus at the end of pregnancy. Apart from the particular situation of non-pregnant animals under progestative influence, in which activity was constantly non-propagated, we could not find any evidence of a general pattern which would indicate only one site for the initiation of activity and its extension to the whole uterus.     

Morinda lucida reduces contractility of isolated uterine smooth muscle of pregnant and non-pregnant mice.

The present work investigated the effect of Morinda lucida (M. lucida) extract on isolated uterine smooth muscle of pregnant and non-pregnant mice. Pregnant and non-pregnant mice were pretreated with oral stilboesterol (0.1 mg/kg body weight) and killed by cervical dislocation. Thin strips of the uterus were cut and mounted in a 20ml organ bath containing De Jalon solution bubbled with 95%O2-5% CO2 gas mixture. The strips were connected to a force transducer coupled to a Grass 7D Polygraph for the recording of isometric tension. Effects of graded concentrations of oxytocin (OXY; 10-5-10-2 mol/L), acetylcholine (ACh; 10-9-10-5 mol/L) and M. lucida extract (0.015-1.5 mg/ml) were recorded. Fresh uterine strips were then incubated with M. lucida extract for 5mins and cumulative response to OXY was repeated. Another set of fresh strips was incubated in L-NAME for 15mins and the cumulative responses to M.lucida extract were repeated. OXY resulted in increased contractile responses in both pregnant and non-pregnant uterine muscles. M. lucida resulted in relaxation of the uterine smooth muscle in both pregnant and non-pregnant mice at all doses. However, at 1.5mg/ml, M. lucida completely blocked spontaneous uterine contractions. Following incubation with L-NAME, M. lucida extract led to a slightly greater relaxation of the uterine strips. In conclusion, M. lucida reduced contractility of uterine smooth muscle in both pregnant and non-pregnant mice as well as blocking contractile responses to OXY and Ach in uterine smooth muscle of pregnant and non-pregnant mice. There was no significant alteration of M. lucida activity by L-NAME suggesting that the action of the compound on uterine muscle is not associated with impaired nitric oxide synthase.     

The sensitivity of the uterus of the mouse and rat to intraluminal instillation

The tissue accumulation of 125I-labelled human serum albumin 30 min after intravenous injection was used as an index of uterine vascular permeability. In ovariectomized mice, all sham and experimental instillation procedures produced a 6-10-fold increase in vascular permeability. Some effects were also manifest in the contralateral, control horn. In ovariectomized rats, instillation of saline and arachis oil increased vascular permeability 3-7-fold. After 3 or more days of progesterone treatment following oestradiol priming, fluorocarbon and arachis oil instillation produced marked vascular responses, but these were not restricted to the transient period in which the uterus would respond with decidualization. An IUD prevented the response to arachis oil instillation. These results indicate that the uterus is very sensitive to any manipulation and are consistent with decidualization representing a specialization of a normal uterine inflammatory response.