M.O. Pulkkinen

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 effect of naproxen-sodium on the prostaglandin concentrations of the menstrual blood and uterine “jet-washings” in dysmenorrehic women☆

Abstract A group of dysmenorrheic women was treated during two consecutive menstrual bleedings, once with placebo and once with naproxen-sodium (naproxen-Na), a potent inhibitor of prostaglandin synthesis. Concentrations of prostaglandins F and E (PGF, PGE) were assayed in the menstrual blood collected into cervical cups, and in uterine “jet-wash” specimens. In the menstrual blood the high PGF concentrations of patients receiving placebo were significantly reduced following treatment with naproxen-Na (from ± S.E. 227±78.9 ng/ml to 42±19.5 ng/ml; p=0.03). A significant decrease of PGE concentrations was also observed during naproxen-Na treatment (from 10.8±2.1 ng/ml to 3.4±1.7 ng/ml; p=0.03). In the uterine “jet washings” naproxen-Na significantly reduced PGE concentrations (p=0.03) while the decrease of PGF concentrations was close to statistical signficance (p=0.06). These results strenthened the premise of causal relationships between naproxen-Na treatment, decreased uterine prostaglandins, reduction of intrauterine pressure, and relief from dysmenorrehic pain.

Progesterone withdrawal during hypertonic saline-induced abortions☆

Abstract In the present collaborative study, 4 independent investigators analyzed 24 samples of plasma from 6 normal obstetric patients. Careful exchange of amniotic fluid with 20 per cent NaCl predictably provoked evolution of uterine activity and abortion. This occurrence has been explained by an induced, partial, progesterone withdrawal.

The relationship between the timing of luteectomy and the incidence of complete abortions

Abstract Earlier studies 1–4 demonstrated that as early as 3 weeks after the missed menstrual period the human placenta already contributes to progesterone (P) genesis to such a degree that it reduces the effect of luteectomy. Therefore, the validity of the premise 5 that luteectomy conducted earlier induces abortion predictably, by provoking rapid and continued P withdrawal and the evolution of intrauterine pressure (IUP) and oxytocin response (OR) was examined. Clinical trials in 8 normal pregnant patients, luteectomized 12.8 ± 1.2 days after the missed menstrual period, verified this expectation. Continued P withdrawal and the evolution of IUP and OR were rapid, and all of the 8 patients aborted in 75.1 ± 4.4 hours, 6 completely and 2 incompletely. The causal relationship between the rate of continued P withdrawal and the subsequent physiologic and clinical events was supported further by the observation that the combined procedures of luteectomy plus salpingectomy (removing the entire conceptus sac in a case of tubal pregnancy) increased the speed of the evolution of IUP, OR, and withdrawal bleeding by further increasing the rate of P withdrawal.

The effect of ibuprofen on the intrauterine pressure and menstrual pain of dysmenorrheic patients.

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.

The effect of estradiol replacement therapy on early pregnant luteectomized patients

Abstract Since in early pregnant patients luteectomy provoked not only progesterone (P) but also estradiol-17β (E 2 ) deficiency, the unlikely possibility that the observed 1,2 physiologic and clinical consequences of the suspension of luteal function resulted from E 2 deficiency had to be examined. Of the 10 luteectomized early pregnant patients studied, uterine activity and reactivity evolved and abortion occurred in those 7 gravidas who had only 18.9 ± 1.9 days of amenorrhea (after the missed menstrual period) and whose plasma P levels decreased continuously. These 7 patients aborted despite the sustenance of preoperative E 2 levels in 6 gravidas by a daily dose of 1 mg. and the increase in E 2 levels in 1 woman by 5 mg. of estradiol bensoate, intramuscularly in oil. In the remaining 3 patients who were luteectomized after 29.7 ± 2.7 days of amenorrhea, plasma P decreased only slightly and not continuously. These 3 patients whose E 2 levels were also sustained exogenously did not abort during 7 days of observation. It is concluded that luteectomy-induced E 2 withdrawal does not but P withdrawal does contribute to the evolution of uterine activity and abortion.

Effect of ibuprofen on menstrual blood prostaglandin levels in dysmenorrheic women

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.

First trimester abortions induced by the extraovular infusion of prostaglandin F2α

Abstract A group of 12 patients, 10.8±0.4 weeks pregnant, received by extraovular infusion 2–4mg/hour PG F2α. Complete abortion was provoked in 7 and incomplete abortion in 2 patients in 9.4±1.5 hours by a total dose of 29.1±3.9mg PG F2α. Three patients failed to abort. A rapid rise in RP was evident shortly after the start of PG F2α infusion. This was followed by a gradual increase in IUP which reached 49.9±3.9mm Hg within 3 hours. Plasma progesterone levels decreased from 31.4±3.0ng/ml to 22.3±2.1ng/ml (P