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The effect of ovariectomy (OVX) and OVX + progesterone (P) treatment on the regulatory profile and uterine function of the guinea-pig are described. Before day 23 of gestation in the intact pregnant guinea-pig, the placental contribution to P-content is small in comparison with the increasing ovarian contribution. After day 30, the ovarian P-content starts to decrease and the placental P-content exceeds the ovarian contribution, indicating the "luteo-placental shift" (LPS) in P-biosynthesis. Thus, when 14 guinea-pigs were ovariectomized around day 21 of gestation all started aborting within 53 hours of OVX. A gradual increase in intrauterine pressure (IUP), a decrease in P-levels in heart and uterine vein plasma and in the uterine and placental tissues and an increase in the levels of PGF in uterine vein plasma and uterine tissue were observed in these animals. However, if the OVX was delayed until after day 30 of gestation, to examine the biological consequences of advanced LPS in P-biosynthesis, there was no increase in IUP and the animals did not abort in the next 5 days. Furthermore, P-therapy following OVX in the day 21 pregnant guinea-pigs prevented the increase in IUP and the animals did not abort. These observations establish for the guinea-pig a correlation between the success in pregnancy maintenance and the degree of the LPS in P-biosynthesis. These studies therefore emphasize the indispensable role of progesterone in pregnancy maintenance.

Forty-eight uterine strips were excised from 24 New Zealand white rabbits and studied in vitro. Sixteen strips were examined when eight animals were 25 days pregnant, 24 strips when 12 animals were about 12 hours postpartum, and eight strips about 12 hours after four animals received a single dose of 5 mg. progesterone (P) at spontaneous delivery. When after repeated exposures to electric fields (60 cycles per second, alternating current, of optimum strength, four seconds' duration at intervals of 30 seconds) the approximately 0.5 Gm. strips developed approximately 40-50g wall tension (WT) in steady state, the field strength was reduced in graded steps from 12 v per 5 cm. to 10, 8, 6, 4 and 3 v per 5 cm. and WT recorded. By measuring the effect on WT of "decreasing electric field stimulation" (DEFS), myometrical excitably and threshold were characterized and quantitated. The technique is based on the relationship between the fraction of myometrial cells activated in the total cell population and WT. As the stimulus is decreased in graded steps from optimal to increasingly suboptimal, DEFS activates fewer and fewer cells reflected by the decrease in WT. Threshold is defined by the strength of the minimum electric field which provokes WT and subthreshold by the field strength which fails to excite. Thus fractional WT averages the excitability of cells in the tissue and thus DEFS characterizes this important parameter of uterine function and quantitates threshold under a variety of regulatory conditions. The comparative study of excised uteri in three different endocrine states showed that the regulatory conditions of normal pregnancy (P levels 9 ng. per milliliter) suppressed excitability and increased threshold (to 6 v per 5 cm.). Post partum (P levels 1 ng. per milliliter) excitability increased and threshold decreased (to 4 v per 5 cm.), unless P treatment prevented this characteristic change by suppressing excitability and increasing threshold (to 6 v per 5 cm.). Both regulatory agents, prostaglandin F2alpha (PGF2alpha) and its analogue ICI 81008, increased excitability and decreased threshold significantly in picogram per milliliter concentrations. However, this effect was observed only when the P levels were low. These compounds had little effect, even in manogram per milliliter concentrations, when the P levels were high. The studies also revealed a close relationship between threshold and spontaneous uterine activity. Low threshold promoted while high threshold suppressed spontaneous activity. In similar concentrations the oxytocic actions of PGF2alpha and ICI 81008 were similar but the effect of ICI 81008 was prolonged through strong binding at myometrical sites.

At the 43rd day of pregnancy 6 Experimental guinea-pigs were treated orally with the PGE1-analogue, CP 48,630 (Pfizer), while 6 animals served as vehicle Controls. An average dose of 1.5 mg CP 48,630 compromized the conceptus and provoked abortion in 6.6 +/- 1.4 hours in all 6 Experimental guinea-pigs. The vehicle Controls, with all pregnancies continuing intact, had high P-levels in peripheral and uterine vein plasma, ovaries, placenta and uterine tissue and low PGF-levels in the uterine vein plasma. In contrast, in the Experimental animals the P-levels were significantly reduced and the PGF-levels elevated. Thus, the "PG-Impact" rapidly tipped the regulatory balance of pregnancy, compromized the conceptus (all fetuses were dead and the placentae discolored), and provoked the evolution of uterine activity culminating in abortion.

Earlier studies1-4 showed that when rats of 10 days' gestation are passively immunized with antiprogesterone (A-P) globulins the biologically available progesterone (P) unbound by A-P (Pu) not only falls precipitously but also remains low for days, despite the rapid clearance of A-P. This finding suggested that the effective reduction of Pu affects P synthesis, probably through action on the fetoplacental unit. If so, pregnancy should be protected from the effect of A-P by P treatment to prevent the reduction of Pu. The present studies demonstrated that if P treatment was delayed for six hours after the administration of A-P, Pu did not return to physiologic levels, and pregnancy did not continue. However, if P was given three hours after A-P, at the same time, or three hours before A-P, the reduction of Pu was short-lived or prevented, and thus pregnancy was protected.

In 87 guinea-pigs the gestational changes were measured in the progesterone (P) and prostaglandin F (PGF) levels of the peripheral and uterine vein plasmas, ovaries, uterus, placenta, fetal membranes and amniotic fluid. In the ovaries, the peripheral and uterine vein plasma, placenta and uterus, P-concentrations increase during early pregnancy and after a plateau decrease significantly as term approaches. In contrast, the uterine-vein PGF-levels remain low throughout pregnancy and only increase near term. Thus, in the guinea-pig, as in the classic species of P-action, normal pregnancy is characterized by high P and low PGF levels and labor by low P and high PGF levels. Of special interest are the additional findings that in the guinea-pig the uterine tissue P-levels are only a fraction of the peripheral plasma levels and the placental PGF-levels far exceed those of the uterus and fetal membranes. To promote the biological interpretation of the endogenous changes in the regulatory profile of the pregnant guinea-pig, current studies examine the functional consequences of the experimentally induced changes in P and PGF-levels.

The concentrations of 15 methyl PGF2 alpha, progesterone and estradiol in the peripheral plasma were assayed sequentially and the resting and active pressures of the uterus were quantitated in 10 first trimester pregnant patients, treated with a vaginal suppository containing 3 mg U-36,384. The purpose of the study was to determine the sequence of the prostaglandin induced changes in regulatory profile and uterine function and thus expose further the mechanism of prostaglandin action. The temporal relationships of the changes revealed that the primary action of exogenous prostaglandin is the disruption of the normal endocrine function of the conceptus and that the delayed oxytocic effect of this compound is secondary, a consequence of the primary action. Apparently prostaglandins are only effective as postconceptional agents if they convert the refractory normal pregnant uterus into a reactive organ. The academic and therapeutic significance of this finding is discussed.

To extend observations in 11 weeks pregnant patients the mechanism of prostaglandin (PG) action has been examined in 6 weeks pregnant women (LMP). In 10 gravidas menstrual induction was attempted with a single slow release vaginal suppository containing 3000 microgram (155)-methyl PGF2 alpha methyl ester (U-36,384). In 10 additional gravidas menstruation was provoked by the intramuscular injection of 500 microgram 16-phenoxy-omega-tetranor PGE2 methyl sulfonylamide (Sulproston) at 4 hour intervals, totalling 1250 +/- 154 microgram. The PGF2 alpha and PGE2-analogues provoked similar changes in hormone levels and uterine function, sequentially measured by radioimmunoassays and the recording of intrauterine pressure. However, the effects of the intramuscular regimen developed earlier. Both treatments successfully terminated early pregnancy with clinical symptoms of menstruation if they irreversible compromised the conceptus within 12 hours. However, while both formulations represent advances in postconceptional therapy, only further modifications may closely approximate the "ideal" method of non-surgical menstrual induction.

Two groups of term pregnant rats, one pretreated with progesterone (P) and another with vehicle only, were induced to deliver with PGF2 alpha. Through an implanted intrauterine (extraovular) catheter 5 microgram PGF2 alpha was injected into each animal every 15 minutes until delivery occurred. If induction fialed the fetuses were removed by hysterotomy. All vehicle controls started delivery within 38.3 +/- 11.7 minutes. In contrast, none of the P-treated rats responded to PGF2 alpha. In all animals uterine vein blood and uterine tissue were collected during labor. Measurements of the P and PGF in uterine vein plasma and uterine tissue showed that the P-treated rats had significantly higher P-levels than the controls (P less than 0.001). In contrast, the PGF-levels were similar in the two groups, but significantly elevated (P less than 0.001) beyond spontaneous labor values. Evidently, the massive elevation of PGF-levels only induces labor when the myometrial action of P is critically reduced and is ineffective when P-action is sustained. Thus, PGF-concentrations cannot be presumed to predict PGF-effect, because the latter is controlled by P.

The Prostaglandin-synthesis inhibitor: Naproxen-Sodium (NS) (an analgesic agent) very significantly (P less than 0.001) reduced the "resting" and "active" pressures and the frequency of cyclic uterine activity of 10 dysmenorrheic patients. It also highly significantly reduced (P less than 0.001) menstrual pain. Since these effects were observed after a single oral dose of 1100 mg NS, without side effects or complications, extensive field trials are recommended for assessing therapeutic benefits of this treatment.

Plasma oestradiol 17beta and progesterone levels in 11 patients admitted to hospital for threatened premature labour of unknown aetiology were compared with those of women at similar stages of gestation whose pregnancy was normal. Oestradiol levels in the study group were slightly higher than in the normal controls but their progesterone levels were significantly lower. This progesterone deficiency increased the oestradiol/progesterone ratio in the study group patients, and it increased still more as the progesterone withdrawal continued during premature labour.Since uterine activity during pregnancy is regulated by a balanced action of several factors a deficiency in progesterone, an opponent of uterine activity, creates a regulatory imbalance which, if uncorrected, provokes premature labour. An increase in uterine volume stimulates uterine activity, and the present study reinforced our previous conclusion that the uterine-volume/plasma-progesterone ratio is a more accurate measure of the state of regulatory balance than the progesterone level alone.The cause of the progesterone deficiency in these cases remains unexplained, but we suggest that placental growth and function are contributory factors. We are investigating ways of correcting the resulting imbalance in the regulatory mechanism.

Studies have elucidated the regulatory interplay between ovarian hormonal changes, prostaglandin levels and the evolution of intrauterine pressure that leads to dysmenorrhea. These studies substantiated the premise that primary dysmenorrhea is caused by endogenous prostaglandin excess and prompted clinical trials with naproxen sodium (Anaprox) in patients with primary dysmenorrhea. The primary action of prostaglandin is constriction of uterine blood vessels, with consequent anoxia and sustained myometrial contraction. Cyclic uterine contractions evolve later but gradually, with the progress of time. However, the cyclic contractions are not perceived as painful. It is important to realize that the source of uterine pain in dysmenorrhea is the high resting intrauterine pressure (tonus). Penetration of excess prostaglandins into general circulation fully accounts for the systemic symptoms of dysmenorrhea (nausea, vomiting, diarrhea, headache, etc). Rational treatment of dysmenorrhea should be directed at elimination of the excess prostaglandin action. Naproxen sodium and other prostaglandin synthesis inhibitors decrease intrauterine resting pressure as well as amplitude and frequency of uterine contractions and reduce the uterine concentrations of prostaglandins. These changes are associated with substantial pain relief. Thus, naproxen sodium and other prostaglandin synthesis inhibitors present a logical treatment modality to be used in dysmenorrhea.

Of a total of 343 pregnant rats treated with the prostaglandin F2alpha analogue ICI 81008, 137 aborted, while 83 had reduced and 123 intact litter. These biological variations depended primarily on the gestational timing of treatment and on the dose and route of administration of this synthetic PG. In comparison with the 107 controls, all experimental rats which aborted had a drastic reduction in plasma progesterone levels which was highly significant (P is less than 0.001) until day 18. In contrast, those animals which escaped suboptimal ICI 81001 treatment with a partly resorbed litter, only had a moderate reduction in progesterone which was statistically significant (P is less than 0.01) until day 16 when levels of this steroid normally begin to decrease. Ineffective treatment did not affect progesterone levels and intact pregnancy. In contrast to progesterone, there was no correlation between plasma estradiol-17beta levels and the consequences of ICI 81008 treatment.

After approximately 2 weeks menstrual delay (positive Pregnosticon Tests) "menstrual induction" was attempted in 75 gravidas by repeated vaginal application of a gel, containing 200 or 400 mug/ml ICI 81008. After approximately 10 minutes, following the 1st vaginal delivery of 400 mug ICI 81008, the uterus responded to this PGF2alpha analogue with sustained contracture. The highest success rate in induced bleeding (93%) and pregnancy termination (79%), without supportive therapy, was achieved when 400 mug ICI 81008 was administered 2 to 5 times at 4 hour intervals. Those gravidas (21%), who failed in induced menstruation, or stopped bleeding within 24 hour- after treatment, had positive Pregnosticon Tests on day 14 and were curetted. The side effects, mostly vomiting and increased blood pressure, were transient and subjectively and medically acceptable. While the vaginal application of the drug is apparently less effective than the intrauterine (1), it has the advantage of simple delivery and the potential of self-administration.

The PGE2-analogue Sulproston (16-phenoxy-omega-17,18,19,20-tetranor-PGE2-mythylsulfonylamide) was administered to 200 medically and gynecologically normal women who were 17 +/- 0.4 days beyond their expected menstrual period and who had a positive pregnancy test. The intramuscular impact dose (500 micrograms repeated after 4 hours) caused an immediate tonic uterine contraction which compromised the estradiol 17 beta, progesterone and chorionic gonadotropin production within the fetoplacental unit, and thereby allowed the evolution of cyclic uterine activity, cervical dilatation and tissue expulsion. Pregnancy termination was complete in 92% of women, 5.5% required surgical curettage and 2.5% were given a second Sulproston treatment 2-3 weeks after the first to remove retained tissue from the uterus. The medical induction of menstruation was preferred by 83% of the women who had previously experienced surgical termination of pregnancy. Normal menstruation resumed in all women after 36 +/- 0.9 days. The majority of 42 women questioned found Sulproston a satisfactory, safe, simple and effective drug regimen for "menstrual induction".

"Menstrual Induction" (MI) has been studied in 79 volunteers, using the therapeutic principle of "PG-Impact". The PGF2alpha analogue: ICI 81008 was administered under strictly aseptic precautions into the uterine cavity during the 4th week of pregnancy. The treatment catheter (inserted through the cervical canal) delivered a single dose of only 100-200 mug ICI 81008 during the pilot study with this new drug. When it was established that the side effects were acceptable, this moderately effective dose was increased at first to 200-300 mug and eventually to 400 mug. At the 400 mug dose level, 29 (76%) of the 38 study patients had complete and 8 (21%) incomplete abortions, while 1 (3%) failed to bleed. Those 9 women who had incomplete abortions or failed to abort were curetted. In comparison with PGF2alpha (428 cases) and PGE2 (114 cases), ICI 81008 (38 cases at the 400 mug level) provoked lesser side effects, excepting the transient increase in blood pressure. All patients (whose intrauterine pressure was measured) responded to the ICI 81008-impact with rapidly developing high level uterine contracture. Plasma progesterone decreased significantly if treatment was successful and insignificantly in cases of treatment failure. In current studies, the efficacy of the vaginal delivery system of ICI 81008 is examined.

In a randomized crossover study 15 dysmenorrheic women were treated during two consecutive menstrual period, once with the potent prostaglandin-synthesis inhibitor: ibuprofen and once with an identical looking placebo. Each patient was medicated for 12 hours during the first day of her menstrual flow and was subsequently fitted with a cervical cup for the collection of menstrual blood during three hours. In these samples the concentrations of prostaglandin (PG)F and PGE were measured by radioimmunoassay. The patients receiving placebo had high PGF levels 135 +/- 27 ng/ml (Mean +/- S.E.) which were significnatly reduced by Ibuprofen to 24 +/- 5 ng/ml (P less than 0.001). The PGE concentrations decreased from 5 +/- 1 ng/ml to 2 +/- 1 ng/ml (P less than 0.05). Ibuprofen also reduced the menstrual pain significantly (P less than 0.001). These results substantiate the earlier conclusion that a causal relationship exists between effective treatment with PG-synthesis inhibitors and decrease in menstrual blood PG levels, intrauterine pressure and dysmenorrheic pain.

Following ovariectomy of five New Zealand white rabbits at day 25 of pregnancy, the intrauterine pressure (IUP) and uterine progesterone (P) and prostaglandin (PG) levels were measured sequentially at days 25, 26 and 27. At day 25, when the uterine P and PGE and PGF were high, massive intrauterine treatment with 500 microng PGF2alpha provoked only a sustained contracture on which only low level oscillation in IUP was superimposed. At day 26, when the P levels had decreased significantly (P less than 0.001) and the PG levels had not changed significantly, 50 microng PGF2alpha significantly increased cyclic IUP as compared with the day 25 value (P less than 0.001). At day 27, when the P levels decreased further, as little as 5 microng PGF2alpha provoked still higher cyclic IUP, in spite of a significant reduction in PG levels (P less than o.05). Stretching the uterus of six post partum and six 26 days pregnant rabbits (after removing the uterine contents) significantly increased the uterine PGF levels (P less than o.001). However, stretch increased only cyclic IUP of the post partum uterus and was without effect on the pregnant uterus, which still had high P levels. These results indicate that the myometrium is activated by exogenous PG or stretch, regardless of whether the uterine PG levels increase, remain unchanged or even moderately decrease, provided that the uterine P levels are reduced to a critical value.

Sixty uterine strips were excised from 8 pregnant and 7 post partum rabbits and stimulated electrically in vitro until they developed maximum isometric tension. The non-steroidal anti-inflammatory agent, Ibuprofen, at concentrations of 125, 250 and 500 microng/ml, significantly reduced tension of the 55 experimental uteri (P less than 0.001) within 7.5 minutes, in comparison with the pretreatment value. Tension in 15 solvent-treated controls remained stable during the same observation period. The reduction in tension was greater in the post partum than the pregnant uteri (P greater than 0.05). Sixteen additional uterine strips, excised from 4 pregnant and 4 post partum rabbits were treated either with 500 microng Ibuprofen or solvent for 7.5 minutes. Radioimmunoassay showed that Ibuprofen significantly reduced the uterine levels of PGF (P less than 0.001) and PGE (P less than 0.001 post partum; P less than 0.05 pregnant) and again the effect was greater in the post partum uteri. These findings suggest that the suppression of uterine function by Ibuprofen is mediated by inhibition of PG-synthesis. In a subsequent study, 36 rats were treated with Ibuprofen on days 20 and 21 of pregnancy, at the ineffective dose level of 4 mg/day and the effective levels of 12, 20 and 30 mg/day. In comparison with the first group, spontaneous labor was significantly delayed in the other three groups (P less than 0.05, P less than 0.01 and P less than 0.001, respectively). In addition, 7 rats were treated with 30 mg/day Ibuprofen and 7 with solvent on days 19 and 20 of pregnancy. On day 21, the Ibuprofen-treated rats showed a significant (P less than 0.001) reduction in the uterine PGF and PGE concentrations, indicating that the prolongation of pregnancy is mediated by an inhibition of uterine PG-synthesis.

The effect of systematically delayed progesterone treatment was examined in 45 pregnant rats near term. Progesterone (P) and prostaglandin F (PGF) were measured in uterine vein plasma and uterine tissue before and during spontaneous labor or during prolonged pregnancy. Control animals exhibited the expected P-withdrawal (Pw) prior to spontaneous labor and properly timed P-treatment predictably prevented Pw and labor. However, when P was administered 11.7 +/- 2.8 hours (Mean +/- S.E.) before spontaneous labor, the animals delivered normally despite increased plasma and tissue P-levels. These observations show that P-concentration can not be equated to P-action. Thus, when high P-levels are measured near term, as in parturient women, the biological ACTION of this hormone on uterine function should be cautiously interpreted.

The effects of PGF2alpha and its analogue ICI 81008 have been compared on the small arteries of the omentum uteri on the rat. The vessels measured 20-80 mum in diameter and were examined by intra-vital-microscopy. While the maximum responses of PGF2alpha and ICI 81008 were similar, the duration of the effect of ICI 81008 was significantly longer (P is less than 0.001). At 15 minutes after the administration of the drugs the effect of ICI 81008 was still almost maximal, while the PGF2alpha response disappeared.

With the "double PG impact" (DPGI) technique in 100 sedated first- and second-trimester volunteers, pregnancy was terminated successfully in 99 with a total extraovular PGF2alpha dose of 19.0 +/- 1.5 mg. in 16.9 +/- 0.9 hours. Two thirds of the patients received only the initial dose of 11.6 +/- 0.5 mg. of PG and aborted in 12.9 +/- 0.7 hours without requiring supplemental treatment. Only mild and transient side effects and 14 indicated curettages were recorded. Excepting one gravida (who failed to abort), plasma progesterone in 99 patients decreased at 3 hours after DPGI from 32.5 +/- 1.7 to 22.7 +/- 1.2 ng. per milliliter (P less than 0.001). The rate of progesterone withdrawal and IAT showed a close relationship and the first-trimester patients aborted at a lower progesterone level than the second-trimester patients (P less than 0.001).

The validity of a new concept, predicting that preterm labor can be induced without oxytocic stimulation by a regulatory imbalance, generated by antiprogesterone (A-P)-provoked P withdrawal (Pw), has been examined in the rat model. At day 19 of pregnancy a single oral dose of the steroidal A-O isoxazol, which inhibits P synthesis, significantly reduced uterine P levels, increased uterine estradiol and prostaglandin F levels, and induced preterm labor. This precocious regulatory imbalance and preterm labor were prevented, by blocking the A-P-induced Pw with P treatment. The regulatory imbalance which triggered the onset of spontaneous labor in the control animals was similar, but it occurred at term rather than before term. The potential of this method in improving the management of medically indicated induction of preterm labor is discussed.

A total of 96, dated pregnant, New Zealand white rabbits were studied. In 58 animals the intrauterine pressure (IUP) of the unstimulated and PGF2alpha-stimulated myometrium was recorded, by the extraovular microballoon technique, before, during and after parturition. In the remaining 38 the concentrations of PGE and PGF and progesterone (P) were measured by radioimmunoassays (RIA). The samples were collected individually or sequentially during the perinatal period from uterine tissue and uterine or peripheral vein blood. At the critical time, at around parturition, when the myometrium is converted from a suppressed and refractory muscle into a spontaneously active and reactive organ (quantitated by recording the IUP), the uterine PGE and PGF levels decreased rather than increased (quantitated by RIA). Thus, this critical regulatory and functional change of the myometrium cannot be accounted for by an increase in the intrinsic uterine stimulant: PG, but only by a decrease in the suppressor: P. These findings, 46 years after the discovery of P, demand the further exploration of Corner's legacy.

Circulating plasma progesterone (P) has been quantitatively controlled in the rat "model" through highly specific binding by treatment with anti-P (A-P). Knowing the constant, which characterizes the binding of P to A-P in plasma, sequential assays of circulating A-P and A-P bound total P (Pt) revealed the levels of the biologically active unbound P (Pu). The studies showed that at different stages of gestation the mechanisms through which A-P reduces Pu and terminates pregnancy are the same. However, the doses of AP which effectively reduce Pu and also the critical levels of Pu at which pregnancy terminates are different. The moderate and transient physiologic P-withdrawal (Pw) at midterm permits the continuation of normal gestation, but pregnancy is terminated by a drastic and sustained reduction in Pu. In contrast, when Pu is only slightly and briefly reduced below physiologic levels, pregnancy continues and only retarded conceptus growth signals that Pw occurred. Apparently Pw has to be controlled and measured with "razor's-edge" precision to fully expose and define the regulatory significance of this steroid in the maintenance and termination of pregnancy. Short of this precision, the key regulator of the pregnant uterus will remain buried, as it has been during 40 years, in controversial findings.

Rats which were subjected to ovariectomy on day 18 of pregnancy and were treated with 17 beta-estradiol underwent delivery prematurely at 0900 +/- 1.9 hours on the morning of day 18. All animals had in plasma and uterine tissue a precipitate and highly significant progesterone withdrawal and a corresponding significant increase in prostaglandin F and prostaglandin F metabolite. Progesterone replacement therapy given to a second group of castrated animals prevented progesterone withdrawal and premature labor, because the hormonal profile in plasma and uterine tissue of these animals was identical with that of the intact pregnant vehicle controls. Electron microscopy of longitudinal and circular myometrial layers showed a precipitate and highly significant increase in the number, size, and area of gap junctions in the uteri of the group undergoing premature delivery. In the uteri of the progesterone-treated and vehicle control groups (both intact pregnant), gap junctions were conspicuously scarce. Thus the extensive regulatory imbalance, provoked by progesterone withdrawal, induced a significant increase in myometrial gap junctions. This structural change established contacts between individual myometrial cell which could transform the multibillion cell community of the uterus into a syncytium, to generate low-resistance pathways to the flow of current and thus promote the propagation of trains of electrical discharge in support of labor.

The relationship between "activator-calcium" (A-Ca), progesterone (P), prostaglandin F2alpha (PGF2alpha) and oxytocin (Oxy) has been examined in 100 uterine strips of 34 pregnant and 100 strips of 34 post partum rabbits. At the 25th day of gestation, uterine P was 13.9+/-1.3 ng/g, while within 3-12 hours post partum 3.3+/-0.3 ng/g tissue (P less than 0.001). Uterine strips, mounted isometrically in Krebs' solution, sustained maximum excitability in a steady state when exposed every 30 seconds for 4 seconds to an electric field of 12 V/5 cm (a.c.). The maximally contracting muscles were then rinsed at intervals of 6 minutes with Ca-free Krebs. In Ca-free Krebs, the post partum uterus lost 31% of its Ca and 96% of its excitability in a short 25 minutes, while the pregnant uterus lost 30% of its Ca and 93% of its excitability in 50 minutes (P less than 0.001). Since the extracellular space is approximately 30% in the uterus, this approximately 30% Ca, lost by both muscles, most probably was extracellular Ca and the small A-Ca fraction which is presumably "bound" more strongly at the membrane systems of the P-dominated pregnant, than the non-dominated post partum uterus. The significantly faster and more complete recovery from Ca-deficiency and inexcitability of the pregnant than the post partum uterus (P less than 0.001), at different levels of external Ca, further substantiates this premise. So does the demonstration that exposure to Ca-free Krebs increases 45Ca-efflux 400% in the post partum and only 110% in the pregnant uterus (P less than 0.001). Exposure to 100 ng/ml PGF2alpha in normal Krebs has a similar effect on the 45Ca-efflux of the post partum uterus, while the response of the pregnant uterus is indistinct (P less than 0.001). These highly significant differences between the post partum and the pregnant uteri in their Ca-efflux explain the higher threshold (P less than 0.001) and lower "sensitivity" to PGF2alpha and Oxy (P less than 0.001) of the pregnant than the post partum uterus. The already very highly significant differences between the two muscles, in threshold and sensitivity to these two most potent oxytocics, were increased still further by rendering the uterine strips Ca-deficient. All together, these findings substantiate the early contention (1-7, 18, 19) that uterine function at the cellular level is regulated by opposing actions of the suppressor P and the intrinsic stimulant PG or other oxytocic agents on threshold, excitability and the Ca-activation of the contractile process.

In 12 dysmenorrheic patients we examined the therapeutic action of the Prostaglandin-synthesis inhibitor: Ibuprofen, a non-steroidal analgesic agent. Ibuprofen highly significantly reduced the resting pressure (P less than 0.001), active pressure (P less than 0.001) and frequency (P less than 0.05) of cyclic activity of the uterus, as well as menstrual pain (P less than 0.001). Since these effects occurred after a single oral dose of 800 mg Ibuprofen, without side effects or complications, extensive field trials are recommended with this and other PG-synthesis inhibitors, to assess their therapeutic benefits.

Nicardipine, a calcium antagonist, suspended the spontaneous activity of the excised rabbit uterus at a concentration of 1 microgram/ml and abolished the electrical excitability at a concentration of 10 microgram/ml. In situ, single doses of 100 and 500 microgram reversibly suspended the spontaneous activity of the postpartum rat uterus (n = 22) for 34 +/- 6 minutes and 94 +/- 9 minutes, respectively. Furthermore, the intrauterine administration of prostaglandin F2 alpha or oxytocin failed to elevate intrauterine pressure in the postpartum rats (n = 18) injected with an average dose of 207 +/- 28 microgram of nicardipine. The administration of nicardipine to the rats (n = 19) immediately after the spontaneous delivery of the first fetus arrested labor, and the delivery of the subsequent fetuses was markedly delayed as compared to the control rats (n = 20). Similarly, when premature labor was induced by ovariectomy (OVX) on day 16, OVX control rats (n = 6) receiving 5 microgram/day of estradiol delivered 82% of the fetuses within 48 hours of OVX, whereas the rats treated with nicardipine (n = 7) delivered only 4% of the fetuses. All fetuses were delivered alive and were normal. Since the estradiol, progesterone, and prostaglandin profiles in the heart plasma, uterine vein plasma, and uterine tissue of the control and experimental rats were similar, the prevention of premature labor resulted from the antagonistic action of nicardipine to calcium.