Studies in the regulation of uterine activity.

IN 1956, Csapo put forward the theory of the local action of placental progesterone in an attempt to explain the separate delivery of human twins, several weeks apart. This theory, which holds that progesterone from the placenta can reach the overlying myometrium by a direct route and produce a functional asymmetry ofthe uterus, has been criticised (Short, 1960) on the ground that such progesterone would be absorbed by the maternal blood stream, and distributed uniformly to the myometrium, thus precluding an asymmetric effect. In order to determine whether progesterone absorbed from an intrauterine site is distributed asymmetrically, we chose the bicornuate uterus as an experimental model, since one horn could be used as a control for the other in the same animal. Finger-cot balloons were inserted into each uterine horn of ovariectomized non-pregnant rabbits. A perforated catheter accompanied each balloon, permitting the introduction of progesterone into the uterine lumen. After the animals had recovered from surgery, the balloons in each horn were filled to an equal volume with water. This volume varied among the rabbits between 2 and 10 ml depending upon the size of the uterus. In each case a final volume was selected which produced a high activity with a resting pressure of not more than 10 mmHg. Progesterone in sesame oil was injected into the lumen of the experimental horn, and sesame oil alone into the control horn. Intra-uterine pressure was monitored before, during and after progesterone treatment. Although both horns underwent a loss of active intra-uterine pressure, the loss was significantly greater (P<0025) and recoverv significantly prolonged, in the horns treated with progesterone. When the technique was applied to pregnant animals, it was possible to induce unilateral deliveries (Porter, 1968). In four rabbits thus treated, the control horns delivered a total of twelve out of fourteen foetuses before the first foetus was delivered from the treated horns. These results can best be explained on the basis that some progesterone reached the myometrium of the treated horn by a direct route, not involving the systemic circulation, and in sufficient quantity to produce a significant difference in the mechanical activity of the two horns. The anatomical basis of this direct route is not known. These results support the feasibility of the 'local placental progesterone' hypothesis since if progesterone from an oil droplet in the uterine lumen can pass through the endometrium to the uterine muscle, it would be expected that steroids secreted by the placenta, which is more intimately related to the myometrium, would also pass directly. Zarrow, Anderson & Callantine (1963) and Schofield (1964) have reported failure to prolong pregnancy in the guinea-pig with systemically administered progestogens. In view of the 'local' theory of placental progesterone, and the fact that the placenta of the guinea-pig is known to secrete progesterone (Heap & Deanesly, 1966), local application of progesterone, or medroxyprogesterone acetate (Depo-Provera, Upjohn) to the uterus of the pregnant guinea-pig, might be expected to prolong pregnancy, where intra-muscular injections failed. Accordingly, pregnant guinea-pigs were given single intra-amniotic injections of large doses of progesterone or medroxyprogesterone acetate (MAP), some 5 or 6 days before term. The results are shown in Table 1.