A.I. Csapo

Effects of luteectomy and progesterone replacement therapy in early pregnant patients

Abstract The effect of luteectomy on the subsequent course of early pregnancy has been further investigated. In patients undergoing tubal ligation, comparisons have been made among those subjected to luteectomy and those receiving progesterone substitution therapy together with luteectomy. Patients exposed to only tubal ligation showed no significant differences from normal pregnant patients in plasma estradiol-17β and progesterone levels and in intrauterine pressure and oxytocin response. In luteectomized patients whose estradiol-17β and progesterone levels decreased markedly and continuously, intrauterine pressure and oxytocin response evolved after operation and abortion occurred. In those patients failing to show a continuous decline in plasma progesterone, only a partial evolution of intrauterine pressure and oxytocin response was evident, and clinical progress proceeded only to incipient abortion. Luteectomized patients treated with progesterone exhibited elevated progesterone and only a slight and transient decline in estradiol-17β levels and no evolution of intrauterine pressure and oxytocin response; normal pregnancy was sustained. Five patients of the 24 studied possessed “corpora accessoria” which were also removed. It is concluded that the evolution of intrauterine pressure and oxytocin response culminating in abortion can be provoked during early pregnancy by luteectomy-induced progesterone withdrawal which only occurs prior to an advanced luteoplacental shift in the site of progesterone synthesis. Progesterone substitution therapy prevented the consequences ascribed to luteectomy.

The significance of the human corpus luteum in pregnancy maintenance: I. Preliminary studies☆

Following the total removal of luteal tissue, circulating plasma progesterone, intrauterine pressure, oxytocin response, and clinical progress in abortion were determined sequentially in 12 first-trimester pregnant patients. 3 patients were ovariectomized for the removal of ovarian cysts and 9 were luteectomized during tubal ligation in an attempt to terminate pregnancy in spontaneous abortion. 7 patients had corpora lutea which averaged 21 plus or minus 1mm in diameter at operation when performed at Day 49 plus or minus 2 (mean S.E.) of pregnancy. These patients responded to ovariectomy or luteectomy by a continuing decrease in progesterone, evolution in intrauterine pressure, oxytocin response, progress in cervical dilitation and, abortion. Abortion occurred with a mean lapse time of 5 plus or minus 1 days after operation. In contrast, 5 patients whose corpora lutea averaged only 11 plus or minus 1mm in diameter when removed at Day 61 plus or minus 4 of pregnancy showed only transient decrease in progesterone after operation. This decrease was followed by an increase in progesterone; no progress in the evolution of intrauterine pressure, oxytocin response, cervical dilatation, and abortion. It appears that so long as the corpus luteum serves as the major source of progesterone, it is indispensable in the maintenance of pregnancy in human subjects as it is in the clinical model animal, the rabbit. However, with the shift of progesterone production from the corpus luteum to the placenta (the luteoplacental shift) the human corpus luteum becomes dispensable. These findings identify the corpus luteum and its secretory product, progesterone, as feasible targets of fertility control strategy.

The prospects of PGs in postconceptional therapy

This is a comprehensive review of the literature dealing with the use of PGs (prostaglandins) to induce labor contractions or abortion. Many graphed bodily responses are used to illustrate the discussion. The functional character of the pregnant human uterus is described. It is theorized, from a review of many studies, that the pregnant human uterus is intrinsically active, but endogenously suppressed. Abortion or labor occur when the suppressor is removed, allowing the intrinsic stimulation within the uterus to operate. The uterus is capable at all times of synthesizing PG; the rate of synthesis depends on the amount of stretch. The administration of PG depends on time for its stimulating effect. Clinical trials have been conducted with various routes of PG administration. Current clinical studies being conducted in the field are reviewed. Evidently, saline solution causes abortion through the same mechanism as PGs, i.e., stimulation of the myometrium. Intrauterine PG therapy will remain the treatment of preference. Work is also being carried out in the mobilization of endogenous PGs.

Peripheral plasma progesterone levels during human pregnancy and labor

Abstract Circulating plasma progresterone levels have been measured in 12 hospitalized, obstetrically normal, nulliparous patients during the last 7 weeks of gestation and spontaneous labor. A total of 92 blood samples were collected sequentially and analyzed by 3 independent investigators using the protein-binding method. Plasma progesterone reached peak values at different times during the last 4 weeks of gestation in individual patients but subsequently decreased slightly with the onset of clinical labor. This finding may be significant, in that it indicates a terminal failure in increased placental progesterone genesis, at a time when thecontinued increase in uterine volume promotes myometrial activity through a stretch effect.

EFFECT OF PROGESTERONE ON THE ELECTRIC ACTIVITY AND INTRAUTERINE PRESSURE OF PREGNANT AND PARTURIENT RABBITS.

Abstract Using a new method, the simultaneous recording of the electric and mechanic activity of the pregnant and parturient rabbit uterus, we obtained detailed information about the character of progesterone effect. When the uterus is effectively blocked by progesterone (endogenous or exogenous) electric activity is greatly suppressed and is restricted to the point of origin. As a result, the mechanic activity of the uterus is insignificant. If the progesterone block is moderately weakened, asynchronic electric activity is generated at different uterine portions but the spread of activity is limited to restricted areas. Mechanic activity improves some-what but carries asynchronic symptoms. When the progesterone block is largely or completely withdrawn, the action potentials generated at the pacemaker area in the form of regular trains readily propagate to distant uterine portions. Electric activity is synchronic resulting in pressure cycles of large amplitude and of uncomplicated shape. The progesterone block is enforced upon the uterus by the endocrine functions of the corpora lutea and placentae. The removal of these endocrine glands results in the withdrawal of the block and the evolution of uterine activity. This evolution can be delayed or reversed by progesterone therapy. Cyclic administration of progesterone results in the cyclic evolution and suppression of uterine activity. The two pregnant horns of the same animal can be made to develop activities of different character and extent. This is achieved by the earlier removal of one set of placentas and their local effect on the emptied horn. The systemic (intravenous) administration of phospholipids also weakens the progesterone block and results in a premature evolution of uterine activity.

Endocrine, structural, and functional changes in the uterus during premature labor

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 delay of spontaneous labor by naproxen in the rat model

Abstract The effects on spontaneous labor of Naproxen, an inhibitor of Prostaglandin synthesis, were examined in 345 pregnant rats. The administration of Naproxen, at the time when the delivery process was already in progress (day 21 of pregnancy) and in doses of 20 mg/kg/day or more, resulted in high incidence of prolonged and interrupted labor, with consequent adverse effects. Naproxen given at a daily dose of 5 to 15 mg/kg, beginning 3 days before term effectively delayed the onset of labor, without evident adverse effects on the gestating animals and the fetuses. Pregnancy was delayed in 98% of the animals and 88% of the fetuses remained undelivered until autopsy terminated the study, 24 hours after the Controls delivered spontaneously. It is concluded that in rats Naproxen effectively prolongs pregnancy and delays labor.

Deactivation of the uterus during normal and premature labor by the calcium antagonist nicardipine

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.

Reversible Sterility Induced by Medroxyprogesterone Injections

150 16-40 year old women divided into 3 groups based on dosage and administration intervals were given injections of 6alpha-methyl 17alph a-hydroxyprogesterone acetate for up to 9 months postpartum to study the drugs contraceptive effectiveness for socially handicapped strongly motivated people. Each group received either 50 100 or 400 mg in each 3-month period. Contraceptive efficiency was 100% during the study. Most common side effects were nervousness irritability nausea weight increase and deviation from normal menstrual cycles. The higher the dose the greater was the deviation from normal menstrual cycles. Menstrual anomalies were reversible. Amenorrhea was well tolerated by the patients who were told it might occur. Endometrial biopsies at the end of treatment showed mild symptoms of endometrial atrophy changing spontaneously to a normal proliferative pattern after a time interval. There were no abnormalities in blood count or kidney and liver function.

The Evolution of Uterine Activity During Human Pregnancy

Recording intrauterine pressure in parturient patients firmly established the fact that uterine activity must reach a certain magnitude in order to initiate and promote clinical progress (Caldeyro-Barcia, 1960; Hendricks, 1960; Burnhill et al., 1962 a; Csapo et al., 1963 a; Csapo, 1964 a). This conclusion stands irrespective of the stage of gestation, the circumstances of the initiation of labor, or even the experimental conditions of the study. However, the methods of recording uterine activity and the analysis of the tracings being different, no general agreement has been reached as to what constitutes labor activity. Yet meaningful quantitation of the intrauterine pressure and the characterization of the quality of uterine activity is mandatory, if pressure tracings are to be used for diagnostic and prognostic purposes, or for the assessment of the regulatory conditions of labor. The biological process through which the uterine activity of labor develops, the “Evolution Process”, is the subject of the present study, prompted by the anticipation that the actiiity of labor may be better characterized by considering the nature of its evolution throughout pregnancy. By this study the complex