Risk of breast, uterine corpus, and ovarian cancer in women receiving medroxyprogesterone injections.

Animal studies have yielded conflicting results on the carcinogenicity of long-acting progestins. Since more than 1.5 million women worldwide are currently receiving injections of a contraceptive progestin, depot medroxyprogesterone acetate, this is potentially an important public health problem. We obtained information on the occurrence of breast, uterine, and ovarian cancer among 5,000 black women attending a metropolitan hospital's family planning clinic who had received injections of medroxyprogesterone for contraception (between 1967 and 1976). The women were followed up for four to 13 years after their initial medroxyprogesterone injection. We compared the observed number of cancer cases in these women with the expected number based on annual age-, race-, and sex-specific rates derived from National Cancer Institute data. During more than 40,000 woman-years of observation, we found no evidence of an increased risk of developing cancer of the breast, uterine corpus, or ovary in these women. After adjusting for possible underascertainment of cancer because of incomplete follow-up, we found the relative risk for medroxyprogesterone users to be 0.7 for breast cancer (95% confidence limits, 0.3 to 1.4), 1.2 (95% confidence limits, 0.1 to 6.7) for cancer of the uterine corpus, and 0.8 (95% confidence limits, 0.1 to 4.6) for ovarian cancer.

Isotonic and isometric responses of different tonic muscles to agonists and antagonists.

1 With isotonic recording the percentage of muscle shortening as compared with the maximal possible shortening, and with isometric recording the percentage of developed tension were determined. In relatively 'thick' muscles, such as dorsal leech muscle, frog rectus abdominis or protractor pharynx of holothuria (0.3-0.8 mm thick), the concentrations of a full agonist (carbachol) producing a given percentage of tension, (e.g. 50%) are about 5 times greater than the concentrations, producing the same percentage of shortening. In 'thin' muscles the difference between the percentage of shortening and tension is either small (retractor dentis of the sea urchin, 0.1 mm thick, response to carbachol) or absent (guinea-pig ileum, 0.06 mm thick, responses to methylfurmethide). The possible mechanism underlying this difference is discussed. 2 With partial agonists (dodecamethonium and heptamethonium) the fractional tension of the frog rectus abdominis is always less than the fractional shortening and the correlation between shortening and tension is the same as in the case of full agonists. 3 The blocking activity of (+)-tubocurarine on the frog rectus abdominis is the same in isotonic and in isometric conditions. 4 On the frog rectus abdominis the alkylating agent, decamethonium mustard, does not produce any 'parallel shift' of the dose-response curve for carbachol, the only result of alkylation being a decrease in maximal response, which is more pronounced in isometric than in isotonic conditions. The degree of decrease is in accordance with the correlation between percentage of shortening and percentage of tension in the absence of alkylating agent. Probably this muscle does not possess any 'spare receptors'. 5 On the frog muscle the dose-isometric response curve for acetylcholine (ACh) is shifted toward greater concentration about 33-fold as compared with the dose-isotonic response curve but after the inhibition of cholinesterases the shift is only about 6-fold. The same shift (5-fold) is observed for carbachol, which is not hydrolysed by cholinesterases. The results with ACh are due to the fact, that after cholinesterase inhibition the sensitivity to ACh increases in isotonic conditions only 13-fold, but in isometric conditions it increases 71-fold. Probably under isometric conditions, when the muscle remains in the extended state, the rate of hydrolysis of ACh is much greater than under isotonic conditions when the muscle is shortened during contraction.

The influence of motor nerve tetanization on the effect of organophosphorus cholinesterase inhibitors on neuromuscular transmission.

1. The changes in the activity of synaptic cholinesterases (ChE) of the ant. tibial muscle in the anaesthetized cat were detected by recording the changes of the blocking activity of acetylcholine (ACh) and comparing them with the blocking activity of carbaminoylcholine (carbachol) injected intra-arterially or intravenously. After the administration of organophosphorus inhibitors (OPI) of ChE the ACh blocking dose diminished 500 to 2000-fold but the carbachol blocking dose did not change. In 4-6 h after the injection of OPI the ACh blocking dose increased again 8 to 15-fold, but the dose of carbachol still remained unchanged. The transmission of high frequency impulses improved after OPI in parallel with the decrease of the ACh blocking activity. Thus the synaptic ChE is partly restored in a few hours after its irreversible inhibition with OPI. 2. Tetanization of the motor nerve (50-60 Hz, 10 min), started simultaneously with the intravenous injection of OPI (armine Gd-42), diminished the impairment of neuromuscular transmission. On the side of tetanization the ACh blocking action was less pronounced and the transmission of high frequency impulses better than on the control side. Thus the tetanization produced some protection of synaptic ChE against inhibition by OPI. The protective effect of tetanization was absent when the tetanization was performed before the injection of OPI or was started 10-20 min after the injection of OPI. 3. The protective effect of tetanization was also observed on the isolated phrenic nerve diaphragm preparation of the rat. 4. The possible mechanisms of the protective effect of tetanization are discussed.

Action of some bisquaternary derivatives of phthalic acids and related substances on neuromuscular transmission.

1. All the bisquaternary derivatives of terephthalic acid with three methyl groups on each nitrogen atom (PK-107, PK-95, PK-97 and PK-126) were depolarizing neuromuscular blocking agents. The most active was the compound PK-97, in which the two quaternary groups are separated by sixteen atoms and are about 20 A (2 nm) apart. Activity was reduced many fold either by decreasing the separation to twelve atoms or by increasing it to eighteen atoms. It was also reduced several hundred fold when one trimethylammonium group in PK-97 was replaced by a hydrogen atom (as in PK-119).2. The presence and position of the ester groups in these compounds is important; depolarizing activity is in most cases greatest when the ester groups are the same distance from the quaternary nitrogen atoms as in acetylcholine, that is, in carbolonium, sebacoyldicholine and PK-154. The monoquaternary analogues of carbolonium and sebacoyldicholine are appreciably active, having between about one-tenth to one-fifth of the activity of their bisquaternary analogues.3. The relationships between the structure and activity of these compounds are discussed, particular consideration being given to the structure of the chain separating the quaternary groups and the arrangement of acetylcholine receptors on cells and of esterbinding groups within these receptors.