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Transcriptomics and proteomics reveal associations between myometrium and intrauterine adhesions.

BACKGROUND: Intrauterine adhesions (IUAs) is a gynecological condition with a poor therapeutic prognosis, that severely threatens the fertility and the reproductive physiology and psychological health of women. Our previous research on the use of umbilical cord mesenchymal stem cells (HUCMSCs) for treating IUAs revealed that CM-Dil-labelled HUCMSCs were barely distributed in the endometrial epithelium. Instead, these cells were predominantly found in the myometrium, with no statistically significant difference in distribution compared to the endometrial stromal cells. Therefore, we aimed to explore the associations between the myometrium and IUAs. METHODS: Eight patients with moderate and 5 severe lesional IUAs were included in the experimental group. The control group included 7 patients whose inner and outer myometrium were normal. We used H&E, Masson's trichrome and immunohistochemical staining to obtain the pathological features of the tissues. Transcriptomic and proteomic analyses were conducted to identify differentially expressed genes, proteins and enrichment pathways. RESULTS: Both IUAs lesion tissues expressed the smooth muscle markers &#x3b1;-SMA and H-caldesmon, and there was no significant difference between severe IUAs tissue and normal myometrium (p&#x2009;>&#x2009;0.05). Transcriptomic and proteomic data revealed that genes and proteins involved in cell mitosis, such as KIF14, KIF4A, and CIT, were downregulated in both IUAs lesion tissues compared with the inner myometrium (p&#x2009;<&#x2009;0.05). Additionally, some genes or proteins that participate in activating the complement-coagulation cascade system and extracellular matrix (ECM) degradation also significantly differed (p&#x2009;<&#x2009;0.05). CONCLUSIONS: Transcriptomic and proteomic data revealed a correlation between endometrial injury and the myometrium. These findings preliminarily revealed that the myometrium possibly contributes to the aetiology and progression of IUAs through dual mechanisms. On the one hand, the myometrium inhibits endometrial regeneration by suppressing the cell mitogenic pathway. On the other hand, it promotes fibrosis by activating the complement-coagulation cascade system and inhibiting the ECM degradation pathway. These new findings increase our understanding of the pathogenesis of IUAs and potentially contribute to the application of precision clinical treatment for IUAs.

Humans

Ultrasonic demonstration of myometrial contractions in intrauterine pregnancy.

An incidental finding associated with ultrasound examination of early intrauterine pregnancy is transient thickening of a limited region of the myometrium, which we interpret as a localized contraction. Contractions were demonstrated in nearly all 881 patients examined and were shown to significantly change in configuration within a 30 min period. In all except one patient, the contractions were completely asymptomatic, and they seem to be of no discernible clinical significance.

Adolescent

Menorrhagia, diffuse myometrial hypertrophy and the intrauterine contraceptive device: a report of fourteen cases.

Fourteen uteri, removed for IUD-associated menorrhagia, were studied. Twelve of these IUD-bearing uteri showed pure diffuse myometrial hypertrophy; the other two uteri were enlarged as a result of multiple leiomyomas in one case and extensive deep adenomyosis in the other. The incidence of pure myometrial hypertrophy in the IUD group was far in excess of that observed in a control non-IUD-bearing menorrhagia series, where leiomyomas and/or deep adenomyosis were mostly responsible for the uterine enlargement.

Adult

Comparison of intrauterine prostaglandin metabolism during pregnancy in man, sheep and guinea pig.

Metabolism of prostaglandin F2 alpha (PGF2 alpha) was studied in uterine tissues from pregnant women (n = 10), sheep (n = 6) and guinea pigs (n = 6). Two maternal tissues, myometrium and decidua or maternal placenta, and two fetal tissues, fetal placenta and membranes, were studied in each species. PGF2 alpha was metabolized via the well-known pathway into 15-keto-PGF2 alpha and 13,14-dihydro-15-keto-PGF2 alpha, while 13,14-dihydro-PGF2 alpha was tentatively identified in some tissues. The presence of 15-hydroxyprostaglandin dehydrogenase (PGDH) and 13,14-prostaglandin reductase was demonstrated in all tissues from each of the three species studied, but the quantitative intrauterine distribution of these enzymes differed from one species to another. In man, PGDH activities were highest in fetal membranes followed by fetal placenta and then by decidua and myometrium. In sheep, PGDH activities were highest in the maternal placenta followed in decreasing order by myometrium, fetal placenta and membranes. In the guinea pig, PGDH activity was highest in the fetal membranes followed in decreasing order by maternal placenta, fetal placenta and myometrium. Quantitative assay of PGDH showed that PGDH activity in the pregnant uterus is higher in women than in sheep and guinea pig. The results are discussed in relation to the involvement of prostaglandins in parturition.

Animals

Some clinical and theoretical aspects on prostaglandins in obstetrics and gynecology.

The present article discusses two aspects on prostaglandins, both related to the control of uterine contractility. One concerns a clinical problem, induction of abortion, and argues in favor of systemic instead of intrauterine administration of prostaglandins and the choice of E instead of F analogues. The other relates to the stimulatory effect on the myometrium of some recently detected endogenous prostaglandins. The discussion regarding the endogenous control of myometrial contractility has so far exclusively been focused upon the classical prostaglandins. It is, however, felt that substances like PGH2, PGI2 and thromboxane A2 may play a significant role in the regulation of uterine activity.

Abortion, Induced

Some effects of an intrauterine device on glucosaminoglycans of the hamster uterus.

The effect of an intrauterine device (IUD) on non-heparin sulfomucopolysaccharide (SMP) was studied in castrated, hormone-treated, and cycling hamsters by photographic densitometry of tissue sections stained specifically for SMP with Alcian blue. Non-heparin SMP increased slightly in the myometrium of IUD-containing uteri of all castrated groups, with the increase being significant in only the peanut oil-treated group. The endometrium also showed slight increases in sulfomucin in IUD-containing uteri of peanut oil, progesterone, and estrogen plus progesterone-treated animals. These increases, however, were not statistically significant. In cycling hamsters the IUD had little effect on uterine non-heparin SMP in most cycle stages.

Animals

Electrical and mechanical activity of rat uterus in vivo during the estrous cycle.

Electromyograms were obtained from three different locations on the uterus of conscious, unrestrained rats during the 4 day estrous cycle. Intrauterine pressure changes were monitored simultaneously by means of indwelling intraluminal balloons (vol. 0.02 to 0.05 ml.). Electrical activity consisted of bursts of action potentials that were usually initiated at either end of the uterus. Propagated burst activity gave rise to cyclic intrauterine pressure changes, whereas bursts appearing at one electrode only did not elicit any measurable contractions. The rate of intrauterine pressure development depended on the propagation velocity, whereas the tension achieved was related to the duration of burst activity. All three parameters of electrical activity studied, namely, the duration and frequency of spike bursts, as well as their rate of propagation, varied significantly during the cycle. Regional differences were also subject to cyclic variations; thus, in proestrus the bursts originated predominantly at the cervical end, whereas in diestrus they were usually initiated at the ovarian end. Oxytocin stimulated the frequency and duration of bursts along the whole uterus and elicited corresponding changes in intrauterine pressure. Response to oxytocin was dose dependent and modified by cycle stage. Norepinephrine caused a transient prolongation of burst activity that was not dose dependent; epinephrine had a marked dose-dependent inhibitory action. The response to catecholamines did not vary significantly during the cycle. The variations in electrical and mechanical activity were characteristic for each stage of the ovarian cycle and could be correlated with the well-known hormonal changes. High circulating estrogen levels in proestrus are associated with infrequent but rapidly propagated spike bursts, whereas low levels in estrus are associated with frequent and sometimes nonpropaged bursts. The rise in plasma estrogen in diestrus coincides with a decrease in the frequency of burst activity, and the elevated progesterone levels are probably causally related to the significant drop in propagation velocity and the increase in duration of bursts observed in diestrus. These findings are consistent with the concept that estrogen withdrawal activates the estrogen-primed, quiescent myometrium, and that progesterone has an effect similar to that of estrogen withdrawal--at least in the rat.

Action Potentials

The effect of aprotinin on luteolytic and uterine contractile mechanisms in the pregnant rat at term.

The effect of the kallikrein inhibitor aprotinin on luteal function, uterine activity and parturition was studied in primigravid pregnant rats. Luteal function was monitored by the determination of serum progesterone levels. Aprotinin given daily from Day 19 to Day 22 of gestation had no effect on progesterone concentrations compared to saline-treated controls, but indomethacin delayed the decline in progesterone levels over the same time period. Aprotinin treatment had no effect on fetal and placental weights from Days 19 to 22 of gestation. Aprotinin infusion in Day-22 pregnant rats resulted in a reduction in uterine motility (studied by continuous recording in conscious rats by means of an intrauterine microballoon) in 10/12 rats. Continuous infusion of aprotinin into rats which had been allowed to deliver one young resulted in a significantly prolonged duration of parturition compared to that in saline-infused controls. In one rat the delivery process was completely arrested and recommended only when the infusion was stopped. Aprotonin had no effect on either the spontaneous or oxytocin-induced uterine contractions of the isolated Day-22 pregnant rat uterus. It is concluded that the kallikrein-kinin system in the late pregnant rat does not appear to be involved in the luteolytic process but may play a functional role in the control of uterine and/or cervical function before and during parturition.

Animals

Anaprox in dysmenorrhea: reduction of pain and intrauterine pressure.

In a double-blind parallel trial, 24 dysmenorrheic women received a single dose of Anaprox (1,100 mg) or placebo. Over the next 2 hours, pain intensity was scored and intrauterine pressure was measured using an immobilized microballoon. At the end of 2 hours, all 11 patients given Anaprox (but only three of the 13 given placebo) experienced complete pain relief (p = 0.0004). The resting intrauterine pressure (IUP) decreased from a mean of 51.4 to 26.8 mm Hg in the Anaprox-treated group, while in the placebo group the mean resting IUP values remained essentially unchanged ( drop from 55.4 to 51.9 mm Hg was observed). This difference between the two treatment groups was statistically significant in favor of Anaprox (p = 0.03). Several patients from each group were given 0.2 mg of ergonovine by intramuscular injection following the 2 hour trial. In both groups, the resting IUP increased within 30 minutes; the corresponding increase in pain intensity was more pronounced, however, in the placebo group. These results support the premise that a decrease in resting IUP is directly linked to the pain-relieving effects of Anaprox.

Adolescent

Prostaglandin-induced luteolysis in pregnant and pseudopregnant rabbits and the resultant effects on the myometrial activity.

The effect of prostaglandin (PG)-induced luteolysis on the myometrial activity in 20--21-day-pregnant and 11--12-day-pseudopregnant rabbits was studied by intrauterine pressure (IUP) recording during PG infusions. The same dose of PG (10 micrograms/h during 8h) was also given to 7 non-pregnant (untreated) does that were used as controls. Peripheral plasma concentration of progesterone and oestradiol-17 beta were measured at 2-h intervals during the infusion. Plasma progesterone level decreased significantly within 2 h or the start of infusion in pregnant and pseudopregnant does and continued to decrease; at the end of 8 h, the concentrations were 31 and 41%, respectively, of the pre-infusion levels. The amplitude of uterine contractions increased significantly after 4 h in pseudopregnant does, increased slightly but insignificantly in the pregnant does and showed no significant change in the non-pregnant does during PG infusion. The amplitudes developed in the pregnant and pseudopregnant does were significantly different. The direct effect of progesterone (1--3 micrograms/h during 4 h) was also studied in 7 non-pregnant rabbits. After 2 h the amplitude of contractions had decreased markedly and the pattern of activity had become irregular. The results support the concept of a myometrial inhibitory factor other than progesterone in rabbit pregnancy and suggest that this factor(s) originates in conceptus.

Animals