Ultrasound image analysis using deep neural networks for discriminating between benign and malignant ovarian tumors: comparison with expert subjective assessment.

OBJECTIVES: To develop and test the performance of computerized ultrasound image analysis using deep neural networks (DNNs) in discriminating between benign and malignant ovarian tumors and to compare its diagnostic accuracy with that of subjective assessment (SA) by an ultrasound expert. METHODS: We included 3077 (grayscale, n = 1927; power Doppler, n = 1150) ultrasound images from 758 women with ovarian tumors, who were classified prospectively by expert ultrasound examiners according to IOTA (International Ovarian Tumor Analysis) terms and definitions. Histological outcome from surgery (n = 634) or long-term (≥ 3 years) follow-up (n = 124) served as the gold standard. The dataset was split into a training set (n = 508; 314 benign and 194 malignant), a validation set (n = 100; 60 benign and 40 malignant) and a test set (n = 150; 75 benign and 75 malignant). We used transfer learning on three pre-trained DNNs: VGG16, ResNet50 and MobileNet. Each model was trained, and the outputs calibrated, using temperature scaling. An ensemble of the three models was then used to estimate the probability of malignancy based on all images from a given case. The DNN ensemble classified the tumors as benign or malignant (Ovry-Dx1 model); or as benign, inconclusive or malignant (Ovry-Dx2 model). The diagnostic performance of the DNN models, in terms of sensitivity and specificity, was compared to that of SA for classifying ovarian tumors in the test set. RESULTS: At a sensitivity of 96.0%, Ovry-Dx1 had a specificity similar to that of SA (86.7% vs 88.0%; P = 1.0). Ovry-Dx2 had a sensitivity of 97.1% and a specificity of 93.7%, when designating 12.7% of the lesions as inconclusive. By complimenting Ovry-Dx2 with SA in inconclusive cases, the overall sensitivity (96.0%) and specificity (89.3%) were not significantly different from using SA in all cases (P = 1.0). CONCLUSION: Ultrasound image analysis using DNNs can predict ovarian malignancy with a diagnostic accuracy comparable to that of human expert examiners, indicating that these models may have a role in the triage of women with an ovarian tumor. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Análisis de imágenes ecográficas utilizando redes neurales profundas para distinguir entre tumores ováricos benignos y malignos: comparación con la evaluación subjetiva de expertos OBJETIVOS: Desarrollar y probar el desempeño del análisis de imágenes ecográficas computarizadas utilizando redes neurales profundas (RNP) para distinguir entre tumores ováricos benignos y malignos y comparar su precisión en el diagnóstico con la de la evaluación subjetiva (ES) por especialistas expertos en ecografía. MÉTODOS: Se incluyeron 3077 (escala de grises, n=1927; power Doppler, n=1150) imágenes de ultrasonido de 758 mujeres con tumores ováricos, que fueron clasificadas prospectivamente por examinadores especialistas en ecografía, de acuerdo con los términos y definiciones de la IOTA (Análisis Internacional de Tumores Ováricos). El resultado histológico de la cirugía (n=634) o el seguimiento a largo plazo (≥3 años) (n=124) sirvieron como el estándar de referencia. El conjunto de datos se dividió en un subconjunto de formación (n=508; 314 benignos y 194 malignos), un subconjunto de validación (n=100; 60 benignos y 40 malignos) y un subconjunto de pruebas (n=150; 75 benignos y 75 malignos). Se utilizó el aprendizaje de transferencia en tres RNP pre-formadas: VGG16, ResNet50 y MobileNet. Cada modelo fue formado primero mediante escalas de temperatura, al igual que los la calibración de los outputs. A continuación, se utilizó una combinación de los tres modelos para estimar la probabilidad de que el tumor fuera maligno con base en la totalidad de las imágenes de un caso determinado. La combinación de RNP permitió clasificar los tumores como benignos o malignos (modelo Ovry-Dx1); o como benignos, no concluyentes o malignos (modelo Ovry-Dx2). Se comparó el desempeño para el diagnóstico de los modelos de RNP, en términos de sensibilidad y de especificidad, con el de la ES para la clasificación de los tumores ováricos en el subconjunto de formación. RESULTADOS: Con una sensibilidad del 96,0%, Ovry-Dx1 tuvo una especificidad similar a la de la ES (86,7% frente a 88,0%; P=1,0). Ovry-Dx2 tuvo una sensibilidad del 97,1% y una especificidad del 93,7%, y designaron un 12,7% de las lesiones como no concluyentes. Cuando se complementó Ovry-Dx2 con ES en los casos no concluyentes, la sensibilidad general (96,0%) y la especificidad (89,3%) no fueron significativamente diferentes de la utilización de ES en todos los casos (P=1,0). CONCLUSIÓN: El análisis de imágenes ecográficas mediante RNP puede predecir el cáncer de ovario con una precisión en el diagnóstico igual a la de los especialistas expertos humanos, lo que indica que estos modelos pueden jugar un papel en el triaje de mujeres con un tumor de ovario. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. METHODS: Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. CONCLUSIONS: Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.

Effect of ovarian steroids on vasopressin secretion.

In normally menstruating women plasma vasopressin concentrations vary with the stage of the cycle and are highest at the time of ovulation and lowest at the onset of menstruation. To determine whether this is the result of changes in the circulating concentrations of ovarian steroids, vasopressin concentrations were determined in six postmenopausal women given oestrogen and progestogen. An increase in plasma oestradiol concentrations to 299 +/- 97.8 pmol/l augmented vasopressin release. Administration of medroxyprogesterone did not influence vasopressin concentrations but when given in combination with oestrogen a fall was observed. Thus it appears that ovarian steroids can modulate vasopressin release.

Variations in plasma concentrations of vasopressin during the menstrual cycle.

Plasma vasopressin concentrations, determined by radioimmunoassay, were followed throughout the menstrual cycle in eight healthy women. The concentrations were found to depend on the day of the menstrual cycle. The mean concentration on day 1 was 0.5 +/- 0.08 (S.E.M.) microunits/ml, while that on days 16-18 was 1.1 +/- 0.16 microunits/ml. These values were significantly (P less than 0.02) different. Vasopressin release in women may thus depend on the hormonal changes during the menstrual cycle.

Synthetic antagonists of the myometrial response to vasopressin and oxytocin.

With the aim of developing inhibitors of vasopressin- and oxytocin-induced uterine activity, 17 analogues of 1-deamino-oxytocin were synthesized by the solid-phase method. Modifications were made at positions 2, O-methyltyrosine (Tyr(OMe] and O-ethyltyrosine (Tyr(OEt],D-Tyr,D-Tyr(OEt),D-Trp; 4, Val,Thr and 8, Orn,Cit,Arg,D-Arg. The analogues were tested for antiuterotonic activity in vitro and in vivo in the rat and in vitro on myometrial strips from non-pregnant women and pregnant women at term. Their selectivity was also investigated in blood pressure and antidiuretic bioassays in rats. Results were compared with those from an original antiuterotonic analogue 1-deamino-2-Tyr(OEt)-oxytocin (d(OEt)-oxytocin). In the rat in vitro and in vivo all analogues possessed higher antiuterotonic activity than d(OEt)-oxytocin. The negative logarithm of the molar concentration of the antagonist which reduced the effect of a dose of agonist to that of half the dose (pA2) was between 7.6 and 8.9 for all the new inhibitors compared with 7.2 for d(OEt)-oxytocin. The highest pA2 value was found for 1-deamino-2-Tyr(OMe)-8-Orn-oxytocin (8.9 +/- 0.2, S.E.M.) and 1-deamino-2-Tyr(OEt)-4-Thr-8-Orn-oxytocin (8.9 +/- 0.6). In myometrium from non-pregnant women the most potent peptide was 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin (17.2 +/- 2.0 times more potent that d(OEt)-oxytocin). In myometrium from pregnant women the inhibitory effects of the majority of the analogues were less pronounced.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma concentrations of vasopressin and a prostaglandin F2 alpha metabolite in women with primary dysmenorrhoea before and during treatment with a combined oral contraceptive.

Oral contraceptives reduce menstrual pain but the interaction with vasopressin and prostaglandin F2 alpha, two uterine stimulants related to the condition, is unknown. Ten women with a history of moderate to severe dysmenorrhoea were studied. Repeated blood samples were taken during a first menstrual cycle without treatment, during the first 21 days of a second cycle when they received an oral contraceptive (150 micrograms levonorgestrel and 30 micrograms ethynyloestradiol) and on the first or second day of the bleeding following hormonal withdrawal. Measurements were made of plasma concentrations of arginine vasopressin, 15-keto-13,14-dihydroprostaglandin F2 alpha, oestradiol-17 beta, progesterone, ethynyloestradiol, levonorgestrel, FSH, LH and prolactin, and serum osmolality was measured. Seven of the women rated their discomfort as moderate to severe on the first two menstruations, but as none or light at the withdrawal bleeding; with the rating scale for degree of pain that was used, this decrease in pain was significant (P less than 0.001). The plasma concentration of vasopressin in these seven women showed significant variation, with the highest concentrations being obtained at the beginning of the two painful menstruations (3.76 +/- 0.76 and 1.75 +/- 0.30 (S.E.M.) pmol/l) and at ovulation in the control cycle (1.91 +/- 0.58 pmol/l). During treatment the concentrations were consistently low, except on the first day of withdrawal bleeding (2.33 +/- 0.35 pmol/l). The concentrations of the prostaglandin F2 alpha metabolite showed less variation, but again the values at withdrawal bleeding (271 +/- 39 pmol/l) were not different from those obtained over the painful menstruations (255 +/- 24 and 217 +/- 25 pmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: To learn more about the beneficial effect of combined oral contraceptives (OCs) on symptoms in primary dysmenorrhea, plasma levels of vasopressin and a prostaglandin F2-alpha metabolite in dysmenorrheic women were investigated before and during treatment with a gestagen-dominated OC. The 10 subjects were administered an OC containing 150 mcg of levonorgestrel and 30 mcg of ethinyl estradiol for 21 days. The 7 women with dysmenorrheic symptoms at the time of blood sampling during the 1st menstruation graded their pain as averaging 2.1 (moderate to severe) + or - 0.3; during the 2nd menstruation, the average value was 2.9 (severe) + or - 0.1, indicating a significant increase in pain at the start of the withdrawal bleeding. Vasopressin concentrations in samples obtained on days 1-3 of the control cycle were significantly higher than those on days 6-8, 20-22, and 24-26 of the control cycle and days 1-2 of the next menstruation. Thus, the highest concentrations were obtained at the beginning of the 2 painful menstruations and at ovulation in the control cycle. During treatment, vasopressin concentrations were consistently low, except on the 1st day of withdrawal bleeding. The concentrations of the prostaglandin F2-alpha metabolite showed less variation, again, values at withdrawal bleeding were not different from those obtained during painful menstruation. Plasma concentrations of ovarian and adenohypophysial hormones, as well as osmolality, were normal throughout. Thus, the present study provided no evidence that there is a reduced release of vasopressin and/or prostaglandin F2-alpha capable of accounting for the beneficial effect of OCs on dysmenorrhea. It is possible, however, that a difference in ovarian hormone concentrations is more pronounced in uterine tissue than in plasma.

Inhibitory effect of O-alkylated analogues of oxytocin and vasopressin on human and rat myometrial activity.

Analogues of oxytocin and vasopressin modified through O-alkylation (methyl, ethyl and butyl) at position 2 of the peptide chain were synthesized and tested for effects on the rat uterus in vivo and on isolated rat and human myometrial preparations. None of the analogues showed any appreciable oxytocic activity. When tested together with oxytocin or vasopressin the analogues inhibited the uterine response to the hormones in a dose-dependent and reversible way. Ethyl-analogues were more powerful antagonists than methyl-analogues but further prolongation of the alkyl-chain (butyl) diminished the antagonistic properties of the compounds. The effect of antagonistic potency of deamination at position 1 of the analogues varied among the analogues and depended on the test system used. The possible clinical value of the antagonists is discussed.

Vascularization of human endometrium. Uterine blood flow in healthy condition and in primary dysmenorrhoea.

The anatomy of the human uterine vascular tree changes repeatedly with the variations in hormonal state during each menstrual cycle, with progressive differentiation of arterioles up to the premenstrual state. Hormonal factors also influence the innervation of uterine arteries, both cholinergic, adrenergic and peptidergic, and regulate the spontaneous contractile activity of the smooth muscle of vessel walls as well as the motor responses of these tissues to different vasoactive substances. The smaller branches of uterine arteries, i.e., the resistance arteries appear to be of particular importance in the regulation of uterine blood flow, since they are most densely innervated. Furthermore, the most effective uterine vasoconstrictors in vitro, vasopressin, endothelin, oxytocin and noradrenaline have a more pronounced effect on these vessels than on the main branches of the uterine artery. Vascular compression may also result from changes in the myometrial activity. A hormonal disturbance may cause dysfunctional bleeding by changing vessel growth as well as the uterine smooth muscle activity of both vessels and myometrium. An example of the latter phenomenon is primary dysmenorrhoea, women with this condition having an increased secretion of vasopressin. By an action on type V1 vasopressin receptors of the uterus, this peptide causes myometrial hyperactivity and vasoconstriction, with resultant uterine ischemia and pain. Further support for a pathophysiological role of vasopressin and also of oxytocin in dysmenorrhoea is the therapeutic effect of a competitive type V1 vasopressin and oxytocin receptor antagonist in the condition.

Vasopressin response and terbutaline inhibition of the uterus.

A study of the effects of 8-lysine vasopressin (LVP) and its long-acting analogue N-a-triglycyl-8-lysine vasopressin (TGVP) on the myometrium and vasculature of the normal human nonpregnant uterus was undertaken. The results suggest that the vasopressins decrease local endometrial blood flow both directly by effects on the uterine vascular bed, and indirectly by increasing myometrial activity. The effects in vivo can be effectively counteracted by beta2 receptor stimulation.

Effects of terbutaline on human myometrial activity and endometrial blood flow.

The selective beta2-receptor stimulator, terbutaline (0.25-0.5 mg), was given intravenously to healthy women at different times in the menstrual cycle. Intrauterine pressure was recorded by means of a microtransducer catheter, and local endometrial blood flow followed by a thermistor technic based on measuring thermodilution. The general response to terbutaline was a decrease in uterine activity and an increase in blood flow. However, the effects varied with the menstrual phase, being maximum around the onset of menstruation and minimum at midcycle. Pretreatment with propranolol (1 mg IV) completely inhibited the effects of terbutaline.

Effects of prostaglandin inhibition on vasopressin levels in women with primary dysmenorrhea.

Arginine vasopressin (AVP) concentrations in plasma were studied in women with primary dysmenorrhea before and after treatment with naproxen, and in healthy control women on the first day of menstruation. In the treated group the AVP concentration was about 4 times higher than that in the controls, and the AVP level remained unchanged after almost complete pain relief had been obtained by treatment with the prostaglandin synthesis inhibitor. No significant differences were found between the 2 groups in plasma osmolality and sodium concentration on the first day of menstruation, or in the concentrations of progesterone and estradiol at this time or in the midluteal phase of the preceding menstrual cycle. These results indicate that increased secretion of AVP may play an etiologic role in dysmenorrhea, activating the uterus via a final step of prostaglandin synthesis an release.

Inhibition of vasopressin effects on the uterus by a synthetic analogue.

A synthetic analogue, deamino-ethyl-oxytocin, which competitively inhibits vasopressin action on uterine activity both in vitro and in animal experiments was developed. The uterine effect of this analogue was studied during the recording of intrauterine pressure in 16 gynecologically healthy women. Increased uterine activity and dysmenorrhea-like pain was induced by infusing lysine vasopressin in a dose of 0.08 microgram/min. Deamino-ethyl-oxytocin inhibited vasopressin action, the threshold dose being approximately 200 micrograms given as a single intravenous injection for about 20 minutes. When given intranasally the drug was also shown to be effective in inhibiting vasopressin-induced uterine activity and symptoms. These results suggest that deamino-ethyl-oxytocin could be of therapeutic value in primary dysmenorrhea, a condition associated with increased vasopressin secretion.

Treatment of cancer patients with a low-density-lipoprotein delivery vehicle containing a cytotoxic drug.

A cytotoxic drug (vincristine, VC) was incorporated into low-density lipoprotein (LDL) and given to cancer patients for the first time by repeated intravenous injection. Individuals presenting with ovarian or endometrial cancer received four or five weekly doses of 1.4 mg/m2 LDL/VC. The uptake of LDL/VC by the adrenal cortex and the liver was minimised by concurrent administration of prednisolone and chenodeoxycholic acid. No febrile, allergic or other reaction attributable to the LDL occurred, and no side effect on haemopoietic, adrenal or liver functions was observed. The neurotoxic side effects commonly seen during VC therapy appeared to be reduced. These results suggest that directed cytotoxic therapy might be achieved in humans through the use of LDL as a carrier. Thus, dose-range and comparative studies using LDL/VC vs VCSO4 are warranted in malignancies in which treatment with the latter drug has been established.

Effects of vasopressin on the human non-pregnant uterus: studies with analogues of different vasopressor potencies.

The uterotonic effects of arginine8-vasopressin (AVP) have been studied on uterine strips from non-pregnant women. Concentration-dependent contractions could be recorded over a 10 min period in the presence of AVP (5.5.10(-10)-3.10(-7) M); the most reproducible recordings were obtained with tissue from the inner part of the myometrium. Analogues of AVP and oxytocin (OT), modified at positions 1 (2-hydroxy-3-mercaptopropionic acid, deamino-3-mercaptopropionic acid), 2 (Phe), 4 (Arg, Val), 7 (Sar) or 8 (Orn) were synthesized and tested for uterotonic activity on human and rat uterine strips, and for vasopressor and antidiuretic activity in the rat in vivo. There was a positive correlation between the activity of these analogues on non-pregnant human myometrial tissue with that in the rat vasopressor assay (r = 0.86, P less than 0.01) but none with their activity in the antidiuretic assay. For example, [Mpa1,D-Arg8]vasopressin had more than twice the antidiuretic activity of AVP but less than 0.2% of its pressor or human uterotonic potency (Mpa = 3-mercaptopropionic acid). Correspondingly, the specific pressor analogue [Hmp1,Phe2,Orn8]OT was as potent as AVP on the human uterus, but had less than 3% of its antidiuretic activity (Hmp = 2-hydroxy-3-mercaptopropionic acid). There was no correlation between the uterotonic activities of AVP or its analogues when non-pregnant human and rat tissues were compared, indicating that rat uterine tissue is a poor guide when testing analogues intended for clinical use in non-pregnant women.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of ketoprofen and naproxen in the treatment of dysmenorrhoea, with special regard to the time of onset of pain relief.

In a double-blind, crossover study in 39 women with dysmenorrhoea, the effects of oral treatment with single doses of 100 mg ketoprofen and 500 mg naproxen were compared with regard to time for onset of pain relief and overall effect on symptoms. Assessments of pain severity using a visual analogue scale and an activity-related scale were made at 15-minute intervals for 2.5 hours. The results showed that ketoprofen was significantly more effective at 60 and 45 minutes, respectively, after intake of medicine and the differences remained significant until 120 and 105 minutes, respectively. Reduction in original pain by 50%, the patient's view on the overall effect after each treatment as well as a comparison of effects at the end of the study all differed significantly in favour of ketoprofen. No significant differences were found between treatments in the need for additional analgesic therapy after the 2-hour observation period or in the incidence of side-effects, which was low with both medications. It is suggested that ketoprofen could have a therapeutic advantage over naproxen, particularly in patients in whom menstrual pain develops rapidly.

Uterine effects of N-alpha-triglycyl-(8-lysine)-vasopressin and 8-lysine-vasopressin in the first trimester of pregnancy.

Myometrial effects of a vasopressin hormonogen (N-alpha-triglycyl-(8-lysine)-vasopressin, TGLVP) and of 8-lysine-vasopressin (LVP) were studied in early pregnancy. Intrauterine pressure was recorded in 28 women, who were to have a therapeutic abortion at 8-12 weeks of gestation, and intravenous injection of TGLVP (0.5 and 1 mg) or LVP (0.1, 0.2 and 0.4 IU) were given, or control recordings without drug injection were obtained. TGLVP generally caused a biphasic increase in uterine activity with a rise in uterine tone as the most conspicuous initial effect followed by an increase in amplitude and duration of contractions. In the higher dose group the uterine activity remained significantly higher than in the controls during the rest of the recording period of 4-7 h. The magnitude of effect with the two doses of TGLVP did not differ significantly. The initial myometrial response to LVP resembled that to TGLVP but the effects disappeared within 10-45 min. In the controls the uterine activity did not change. It is suggested that vasopressin analogues could have a therapeutic value in the induction of abortion, but further basic studies are required to define this.

Comparison of plasma and myometrial tissue concentrations of estradiol-17 beta and progesterone in nonpregnant women.

Plasma and myometrial tissue concentrations of estradiol (E2) and progesterone (P) were measured by radioimmunoassay techniques in samples obtained from women with regular menstrual cycles and from women in pre- or postmenopausal age. In women with regular cycles, the tissue concentration of E2 ranged from 0.13 to 1.06 ng/g wet weight, with significantly higher levels around ovulation than in follicular or luteal phases of the cycle. The tissue concentration of P ranged from 2.06 to 14.85 ng/g wet weight with significantly higher level in luteal phase than in follicular phase. The tissue/plasma ratio of E2 ranged from 1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal phase. The ratio for P ranged from 0.54 to 23.7 and was significantly lower in the luteal phase than in other phases of the cycle. One woman in premenopausal age with an ovarian cyst was the only case with a tissue/plasma ratio of E2 Less Than 1, since her plasma E2 levels were exceptionally high. In postmenopausal women, the tissue concentration of E2 was not significantly lower than in menstruating women in follicular phase, and the tissue concentration of P was not significantly lower than in fertile women in any of the phases. Neither in these women nor in menstruating women was there a close correlation between tissue and plasma levels. The present data indicate that the myometrial uptake capacity for ovarian steroids may be saturated, and also that a certain amount of these steroids is bound to tissue even if plasma levels are low.

Influence of copper ions on uterine activity.

The influence of copper ions on myometrial activity was tested in nonpregnant rabbits in vitro and in vivo, and nonpregnant women in vivo. In an organ bath, CuCl2 in concentrations of 3 micro M and higher caused a dose-dependent increase in the contractile activity of isolated rabbit myometrium. In rabbits in vivo, intrauterine instillations of 0.2 to 2 mM of CuCl2 in 0.6 ml of saline solution caused a dose-dependent increase of myometrial activity in the uterine horn where it was injected, and the response lasted up to 30 minutes. The activity in the other horn remained unchanged and control injections with saline had no effect. Also, in nonpregnant women, a clear and dose-dependent effect of 1 ml of 0.3 to 3 mM of CuCl2 dissolved in saline was observed after intrauterine instillation. Saline itself in the same volume had no effect. It is estimated that the intrauterine doses of copper which were used in these experiments lead to Cu++ concentrations in the uterine tissues which were similar to those in women carrying a copper IUD, and it is suggested that the copper from such IUDs might have effects on myometrial activity contributing to the contraceptive action and to some of the side-effects of these devices.

PIP: A study was conducted to determine the influence of copper ions in nonpregnant rabbits "in vitro" and "in vivo" and in nonpregnant women "in vivo." 25 nonpregnant does of Polish strain were housed under standardized conditions of light and feeding. Myometrium from 10 rabbits was used for "in vitro" experiments; the other animals were studied "in vivo." 6 nonpregnant, parous, and gynecologically healthy women of reproductive age participated in the study. The experiments were done within 3 days before onset of menstruation, and the recording sessions lasted for about 3 hours. In the nonpregnant rabbits "in vitro," a clear increase of the amplitude and frequency of contractions was observed with concentrations of CuC12 as low as 3 mcM in the bath fluid. An elevation of the basal tone was observed and with concentrations of 30 mcM and higher a sustained contraction generally occurred. Intravenous injections of 1 ml of CuC12 solution at a concentration of 2mcM were given to 5 rabbits "in vivo." There was no consistent effect on myometrial activity or on arterial blood pressure. A volume of 0.6 ml of saline per se had no effect on the uterine activity in 10 "in vivo" rabbits. CuC12 dissolved in the same volume of saline in concentrations of 0.2 mM resulted in an increase in uterine activity in the majority of rabbits. With 2.0 mM of CuC12 the effect was pronounced in all does. In nonpregnant women a clear and dose-dependent effect of 1 ml of 0.3-3 mM of CuC12 dissolved in saline was observed after intrauterine instillation. Saline itself in the same volume had no effect. It is estimated that the intrauterine doses of copper which were used in these experiments lead to Cu++ concentrations in the uterine tissues which were similar to those in women carrying a copper IUD. The copper from such IUDs might have effects on myometrial activity contributing to the contraceptive action and to some of the side-effects from copper IUDs.

Effect of an oral contraceptive in primary dysmenorrhea--changes in uterine activity and reactivity to agonists.

Mechanisms for the therapeutic effect of oral contraceptives in dysmenorrhea were studied by recording intrauterine pressure on the first day of menstrual bleeding in women with moderate to severe symptoms and after three weeks of oral contraceptive therapy (150 micrograms levonorgestrel + 30 micrograms ethinyl estradiol, daily). Spontaneous uterine activity and reactivity to intravenous injections of vasopressin (6 pmol/kg body weight; n = 8) or prostaglandin F2 alpha (12 nmol/kg body weight; n = 9) at the two sessions were compared. During the first recording when all women had dysmenorrhea, the uterine activity and reactivity to both agonists were pronounced. After therapy, when the women felt essentially no pain, a statistically significant decrease in spontaneous uterine activity in terms of total pressure area, frequency and amplitude of contractions was observed. The agonist injections induced less pain at the second recording, although the magnitude of responses, superimposed on the much smaller uterine activity at this time, were not significantly different from those at the first recording during dysmenorrhea. The mechanism of pain relief by oral contraception in dysmenorrhea could be a lesser impact of the decreased contractile activity on uterine blood flow, abolishing the local ischemia. A reduced uterine reactivity to agonists might also to some extent contribute to the therapeutic effect.

Potential use of oxytocin and vasopressin V1a antagonists in the treatment of preterm labour and primary dysmenorrhoea.

In order to study the involvement of oxytocin (OT) and vasopressin (AVP) in mechanisms of uterine activation and to clarify the therapeutic potential of antagonists to these hormones in preterm labour and primary dysmenorrhoea, studies of human uterine contractility in vivo and in vitro as well as measurements of OT and AVP V1a receptors were performed. Good correlations between OT receptor concentrations and effects on contractility were observed in both the pregnant and non-pregnant states, which indicates that OT acts specifically on its own receptor in the uterus. For AVP there was lack of such correlation which may suggest that this hormone influences both the OT and AVP V1a receptor sites. At the onset of labour both preterm and at term no marked increase in the OT receptor concentration was observed, but OT may still be involved in the initiation of labour, being produced locally in the uterus and not detectable in plasma. We observed a reduced OT receptor concentration in advanced labour and after OT infusion, which suggests that OT influences its own receptor. The AVP V1a receptor concentration and the effect of AVP on the uterus were about equal to those for OT, and the concentration of AVP V1a receptors also tended to decrease in advanced labour, observations which support an involvement also of AVP in the mechanisms of labour. In non-pregnant women AVP receptors as well as uterine effects of AVP in vitro and in vivo were about five times higher than those for OT, and the effect of AVP was increased premenstrually. This firmly supports an aetiological role of this peptide in the uterine hyperactivity of primary dysmenorrhoea. We have also shown that the analogue 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-OT, which blocks both the OT and AVP V1a receptor sites, given by intravenous infusion inhibits both preterm labour and dysmenorrhoea, and this is in agreement with our receptor and contractility findings.