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Chronic (17 to 20 weeks) administration of ethinyl estradiol alone (36 mug/kg/day), and in combination (27 or 50 mug/kg/day) with several doses of norethynodrel (135, 165 or 233 mug/kg/day), attenuated the increase in heart rate accompanying acute SC administration of the beta-adrenergic agonist, l-isoproterenol (50 or 100 mug/kg), to female rats. Dietary administration of an oral contraceptive containing mestranol and norethynodrel (7.5 mg/kg/food) was also accompanied by an attenuated response to isoproterenol. A significant inverse linear relationship was observed between the logarithm of the dose of estrogen received by each group and either heart rate or change in heart rate measured at 10, 20 and 30 min after administration of isoproterenol. Thus, the antagonistic relationship between the dose of estrogen administered chronically and responsiveness of heart rate to a test dose of isoproterenol suggests a reduced beta-adrenergic responsiveness in estrogen-treated rats.

The serum level of pregnancy-associated alpha2-globulin was studied in 70 healthy women taking three different types of oral contraceptives [40 Bisecurin: containing 1.0 mg of Ethynodiol diaceticum +0.05 mg Ethynilestradiol; 20 Infecundin: containing 2.5 mg of Norethynodrel +0.1 mg of Mestranol; 10 Cervicundin: containing of 0.5 mg Ethynodiol diaceticum]. Elevated amounts of serum level of pregnancy associated alpha2-globulin could be detected in 37 of the 40 women taking Bisecurin and in all 20 taking Infecundin. Cervicundin however, failed to induce any change in the serum protein pattern of the 10 subjects studied. Serum levels of pregnancy-associated alpha2-globulin were higher in the Infecundin-taking (53 mg %), than in the Bisecurin-taking group (29 mg %). This shows the oestrogen dependency of the pregnancy-associated alpha2-globulin and points to a possible implication of this globulin in the immunosuppressive processes.

Female rats treated chronically with ethynylestradiol (36 micrograms/kg per day) alone, and in combination with the progestational agent, norethynodrel (253 micrograms/kg per day), cooled significantly faster than controls when lightly restrained and exposed to air at 5 degrees C. Rate of cooling of rats given only norethynodrel was similar to that of the control group. In other studies, rate of oxygen consumption was determined for all groups during acute exposure to cold (14 degrees C). All estrogen-treated groups achieved the same maximal rate of oxygen consumption as control and norethynodrel-treated groups during cold exposure, but cooled significantly faster. Two groups of female rats were treated chronically with ethynylestradiol at two separate doses (36 and 61 micrograms/kg per day). An untreated group served as controls. Rate of oxygen consumption of all animals were measured during restraint and exposure to cold (18 degrees C). The estrogen-treated groups again achieved the same maximal rate of oxygen consumption as the control group, but also cooled significantly faster despite the fact that the cold stress was less severe than in the previous experiment. That estrogen-treated rats cooled faster than controls in both studies despite achieving a maximal rate of heat production which did not differ from controls suggests that reduced cold tolerance of estrogen-treated rats may be related to increased heat loss.

Liver tumor formation in rats treated with oral contraceptive steroids for long periods has been associated with the tumor promoting potential of these agents. As other known liver tumor promoters, e.g., phenobarbital and hexachlorocyclohexane, induce liver growth and hepatic monooxygenases, we investigated whether or not estrogens have similar effects. Female rats were treated with a wide range of doses of ethinylestradiol, including human contraceptive doses, which are approximately 1 microgram/kg. The physiological estrogen estradiol was studied for comparison. Also included were norethynodrel and norethisteron and its acetate and enanthate because these human progestins act predominantly estrogenic in rats. Daily s.c. doses of ethinylestradiol (0.5 mg/kg) produced a rapid increase of liver mass, DNA, RNA, and protein which was almost maximal after 7 days. The percentages of parenchymal cells involved in DNA synthesis and mitosis were enhanced up to 20-fold, suggesting parenchymal hyperplasia as the main cause of liver growth. Sinus wall cells showed a proportionate increase of number and DNA synthesis. Likewise, all other steroids tested produced significant increases of liver mass and DNA. For ethinylestradiol and estradiol extrapolated threshold doses were in the range of 1 microgram/kg. These doses are below those used in previous tumor promotion studies in rats. Using 5 different substrates to check monooxygenase activities of isolated liver microsomes, no induction or only very weak induction by estrogens was found. These studies suggest that induction of liver growth may be a property relevant for the tumor promoting activity of estrogens; in contrast, induction of hepatic monooxygenases does not appear to be necessary for liver tumor promotion in the rat.

Administration of the estrogen, ethinyl estradiol (36 microng/kg/day), alone, and in combination with the progestogen, norethynodrel (165 microng/kg/day), significantly attenuated the dipsogenic response characteristically induced by acute s.c. administration of the beta adrenergic agonist, dl-iosproterenol (50 microng/kg). Attenuation was apparent within 1 week of steroid treatment, and remained during the 4 weeks of testing. After 16 weeks of steroid treatment, the drinking response to acute i.p. administration of renin (2 and 4 Goldblatt units/rat) was tested. The groups receiving ethinyl estradiol alone, and in combination with norethynodrel, but not norethynodrel alone, showed a reduced water intake compared with untreated controls. Drinking induced by administration of hypertonic saline (1% of body weight of 1 M NaCl solution, i.p.) was also reduced in rats treated with the estrogenic, but not the progestational, agent. However, estrogen treatment did not affect drinking after a 24-hour period of dehydration. Although the reduced dipsogenic response to isoproterenol observed in estrogen-treated rats may reflect a reduced renin secretion, drinking could not be induced in these animals by administration of renin. In addition, the reduced dipsogenic response to hypertonic NaCl loading suggests that estrogens may inhibit thirst mechanisms centrally. Dehydration, which combines hypovolemic and osmotic thirst situmul was, however, sufficient to overcome the reduced dipsogenic responsiveness of estrogen-treated rats.

An enhanced development of pituitary tumors was observed in virgin female mice of the C57 Leaden strain following repeated oral administration of synthetic progestins. This finding appears to parallel the co-carcinogenic enhancement of mammary tumor development elicited in C3H mice treated repeatedly with progesterone.

Acute phase protein precipitating sonatic C-polysaccharide of pneumococci appears in serum of women under treatment with hormonal contraceptives in a significantly higher number of cases when compared with control groups. The summarized results of three preliminary studies show that in 80 control serums there were four positive specimens (5 percent) and in 80 serums from women using hormonal contraceptives there were 58 positive specimens (72.5 percent).