Effect of ethynodiol diacetate with ethinyl estradiol on the mammary glands of rhesus monkeys: a preliminary report.

The oral contraceptive combination of ethynodiol diacetate with ethinyl estradiol (Demulen) was given cyclically to 48 female rhesus monkeys for 5 years. Doses employed were 1, 10, and 50 times the human dose. Treatment did not induce palpable breast nodules, and there were no deaths from mammary gland cancer.

Effect of oral contraceptives on the mammary glands of Rhesus monkeys: a preliminary report.

PIP: To determine the relationship of oral contraceptive use and breast cancer, 96 rhesus monkeys were administered either Enovid-E (2.5 mg norethynodrel and .1 mg mestranol) or Ovulen (1 mg ethynodiol diacetate and .1 mg mestranol) cyclically for 5 years at doses of 1, 10 and 50 times the human dose. The animals' progress was compared with a control group of 32 monkeys. General physical and mammary gland examinations were conducted before treatment and monthly thereafter. During the 5 year study period none of the treated animals demonstrated clinical evidence of mammary gland lesions, no deaths from breast malignancy occurred, and no palpable breast nodules were found.^ieng

Ocular effects of oral contraceptives. I. Studies in the dog.

The administration of two oral contraceptives to female dogs for 5 years did not produce ocular lesions. Corneal and lenticular opacities occurred with equal frequency in control and treated groups, and fundic lesions, including papilledema, venous dilatation, and venous or arterial retinal thrombosis, were not produced by doses of Enovid-E or Ovulen 1, 10, and 25 times the human dose.

Ocular effects of oral contraceptives. II. Studies in the rhesus monkey.

Oral contraceptives were administered cyclically to 96 female rhesus monkeys for 5 years. Forty-eight animals received Enovid-E and 48 were treated with Ovulen at doses 1, 10, and 50 times the human dose. Ophthalmic lesions did not occur at any of the dose levels employed. Significant fundic lesions, including papilledema, venous dilatation, venous retinal thrombosis, or arterial retinal thrombosis, did not develop in any of the treated animals.

Incidence of venous thromboembolic disease in nonpregnant women of childbearing age.

Data from 12 Cincinnati hospitals were examined to determine the incidence of venous thromboembolic disease in nonpregnant women of reproductive age. The incidence of superficial and deep vein thromboembolic disease in women age 15 to 44 was 1.09 cases per 1,000 women per year; for women age 20 to 44 the incidence was 1.3 cases for 1,000 women per year. These figures include idiopathic and non-idiopathic cases and thus are representative of the general population of nonpregnant women of reproductive age. The incidence of pulmonary embolism was approximately 1 case per 5,000 women age 20 to 44. There were two deaths from pulmonary embolism, giving a mortality rate of 11.3 deaths per million women age 15 to 44.

Relationship of estrogens and oral contraceptives to endometrial cancer in animals and women.

PIP: Various experimental and clinical studies have been made to evaluate possible relationships between estrogen and endometrial cancer. Estrogens do not induce endometrial carcinoma in most species of laboratory animals. In contrast to the limited species effect of estrogen, known carcinogens such as 2-naphthylamine, nitrosamines or aflatoxin B1 produce tumor incidence in a variety of species. Some case-control studies provide the hypothesis that estrogens in menopausal or postmenopausal women may be associated with increased risk of endometrial carcinoma. These studies provide only for association, and the theory of direct relationship must be confirmed or denied by more direct measurements. Other data on estrogens do not show a relationship between estrogens and endometrial cancer. Cases of endometrial cancer have been observed in women using sequential oral contraceptives, particularly dimethisterone with ethinylestradiol, but a cause-and-effect relationship has not been established. Progestins may arrest the progress or cause regression of endometrial carcinoma, but the indications are that the progestin is not protective against the carcinoma in the dosage employed. No data indicates that combination oral contraceptives cause endometrial cancer. The progestin in combination oral contraceptives may offer some protection against endometrial neoplastic changes.^ieng

Evaluation of the carcinogenic effects of estrogens, progestins and oral contraceptives on cervix, uterus and ovary of animals and man.

Estrogens do not have the general biological effect of increasing the occurrence of cancer in various species of laboratory animals. The neoplastic effect of estrogens in animals is strain and species dependent. Estrogens may increase the incidence of uterine cervical cancer in some strains of mice, but not in other strains or other animal species. The progestins and oral contraceptives (OC) have not induced cervical cancer in animals and most studies demonstrate that the steroid anovulants do not increase the occurrence of abnormal cervical smears or cervical cancer in women. Estrogens increase the occurrence of endometrial cancer in the rabbit, occasionally in the mouse, but apparently not in other species. Case-control studies in menopausal and postmenopausal women indicate an increased risk of endometrial carcinoma (EC) associated with use of estrogen. However, in other studies estrogen has not been related to EC. Cases of EC have been reported in women using sequential OC but a causal relationship has not been established. Progestins alone may arrest progress or cause regression of EC in women. EC has not been related to use of the combination OC, and it is unlikely that use of these anovulants will lead to the development of endometrial cancer. Estrogens or OC do not induce a carcinogenic response in the ovary. A decrease in ovarian cysts, is observed during the clinical use of OC.

Effect of estrogens and progestins on the cervix uteri.

High doses of estrogen may increase the occurrence of cervical cancer in mice but not in the rat, dog, or rhesus monkey. Available data do not demonstrate that estrogens increase the frequency of cervical cancer in women. Thus, studies in the mouse did not predict correctly for women. The effects of progestins and oral contraceptives on the cervix of various species are also reviewed.

Oral contraceptives: relations to mammary cancer, benign breast lesions, and cervical cancer.

The results of experimental studies on the relationship of estrogens and oral contraceptives to mammary lesions demonstrate that the type of response obtained depends largely on the species and strain of animal that is employed. A variety of clinical studies has failed to demonstrate that estrogen can cause mammary cancer, this lack of effort correlates with the results obtained in various studies in animals. Similar relationships exist for oral contraceptives, and the clinical data show good agreement in demonstrating that the contraceptive steroids do not have a tumorigenic effect on the human mammary gland. Estrogen can increase the occurrence of cervical cancer in certain strains of mice, but apparently this effect is not observed in other species of animals, including man. The preponderance of data shows that oral contraceptives do not adversely affect the occurence of abnormal Papanicolaou smears, cervical dysplasia, cervical cancer in situ, or invasive cervical cancer.

PIP: The clinical and experimental literature on the relation of estrogen, progestins, and oral contraceptives (OCs) to breast cancer, benign breast lesions, and cervical cancer is reviewed. Experimental studies on the relation of estrogens and OCs to mammary lesions indicate a varying response that largely depends up on the species and strain of animal studied. Various clinical studies have failed to show that estrogens or OCs cause breast cancer; similar findings have been reported in animal studies. Estrogen has been found to increase the incidence of cervical cancer in certain strains of mice, although such an effect has not been demonstrated in other species and man. Most studies agree that OCs do not adversely affect the incidence of abnormal Papanicolaou smears, cervical dysplasia, cervical cancer in situ, or invasive cervical cancer. Progesterone has effectively brought about remission in cases of cervical cancer, as have progestins in cases of breast cancer.

Benign cholestatic jaundice of pregnancy and benign cholestatic jaundice from oral contraceptives.

PIP: A discussion of benign cholestatic jaundice of pregnancy and from oral contraceptives is presented. It has been established that recurrent cholestatic jaundice of pregnancy is caused by interference with liver secretory processes such that conjugated bilirubin accumulates in the blood stream. The condition maybe caused by a possible inherited metabolic effect resulting in an increased secretion of estrogen and progesterone. Women with a history of cholestatic jaundice of pregnancy may experience generalized pruritus or cholestatic jaundice if they are on an oral contraceptive regimen. Pruritus may be a symptomatic sign of the onset of cholestatic jaundice and in women using oral contraceptives, the condition indicates the possible development of choletic jaundice during pregnancy. Cholestatic jaundice will usually disappear 1 to 8 weeks after parturition or the cessation of oral contraceptive therapy.^ieng

Interspecies response to carcinogens and oestrogens.

PIP: Several chemical compounds have been proven to have a tumorigenic effect in a number of different animal species. Estrogens, on the other hand, do not produce comparable effects in several different species, or a response of the magnitude that is characteristic of a carcinogen; indeed a positive effect of estrogen is restricted to certain situations. It is often stated, for example, that estrogens cause breast cancer, but it is not stated that the effect is confined to male mice from specific inbred strains that possess a mammary tumor virus. The effect of estrogens in the female rat is variable; it may be without effect, or it may produce mammary cancer in as many as 27% of the treated animals. Many clinical studies do not demonstrate a relationship between exogenous estrogens and breast cancer. Similarly, the effect of estrogen on the uterine cervix or the endometrium of different animal species does not demonstrate a carcinogenic profile. The effect of estrogen is strain- and species-dependent, and when a positive response is obtained only a small proportion of the treated animals are affected, which is not typical of a carcinogen. Thus, definite conclusions on the carcinogenic effects of estrogens are not possible.^ieng

Antifertility drugs. Introductory remarks.

PIP: The introductory remarks on the subject of antifertility drugs made by V.A. Drill at the 1970 Pharmacology Society Symposium are presented. The development of oral contraceptives is described. It is noted that oral contraceptives were develoepd coincident with the increasing public awareness of the "population explosion". At a certain point in the population growth, the public interest will become manifest, and each nation will establish a population policy. Among the papers presented at the symposium will be 2 by Dr. Saunders and Dr. Goldzieher, which review certain of the basic and clinical studies performed with oral contraceptives. Dr. Rudel will discuss the low-dose progestins. Drs. Duncan and Pharris will describe new approaches which are currently being explored. Ultimately, in order to control world population effectively, an immunological treatment may be required whereby 1 injection will control fertility for 2.5, or even 10 years. Dr. Garcia will summarize papers on this area of study.^ieng

Thromboembolic disorders and oral contraceptives (author's response).

PIP: In refuting the challenge of Doll, Inman, and Vessey to the results that oral contraceptives failed to be related to thromboembolic disease, the following arguments were made: 1) the British study was based on only hospitalized patients with and without thromboembolic disease, 2) the sample involved a relatively few number, 3) predisposing conditions must be considered, and 4) the rise in death rates for venous thromboembolic disease in England and Wales among both men and women cannot be explained simply by oral contraceptive use. The large scale studies with oral contraceptives by the authors failed to show the relationship to thromboembolic disease when the observed incidence rates are compared with control rates based on patient visits to the doctor, hospital admissions, or the low rate during pregnancy.^ieng

Estrogens: why harmless as menopausal therapy but hazardous in the "Pill"?

PIP: An inquiry as to why the use of estrogens in large doses has been sanctioned in a variety of therapeutic situations and condemned when used in smaller doses as contraceptives is answered by 2 consultants. Dr. C.C. Edwards of the U.S. Food and Drug Administration answers that there is considerable difference between the conjugated equine estrogens used in therapy and the synthetic estrogens, ethinyl estradiol and mestranol, used in contraceptive medications. The same menopausal symptoms relieved by 1.25 mg of conjugated equine estrogens daily require only .02 mg of ethinyl estradiol. .05 mg ethinyl estradiol daily has a potent ovulation inhibiting effect while 3.75 mg of conjugated equine estrogens daily is ineffective in inhibiting ovulation consistently. Oral contraceptives with .02 mg of ethinyl estradiol might be virtually without serious estrogenic adverse reactions, but studies to date have shown .02 mg daily to be ineffective as an ovulation inhibitor. Dr. V.A. Drill of G.D. Searle and Company contends that the British investigators who reported an increased incidence of thromboembolism in oral contraceptive users compared the estrogens taken simply on a milligram basis rather than in relationship to their estrogenic potency. Errors were also made statistically. Dr. Drill asserts that the controversy regarding thromboembolic disease which followed the British announcement is not based on established facts. Early appraisals of the possible role of different doses of mestranol and ethinyl estradiol in the British study are premature.^ieng

Is absorption of oral contraceptives affected by intestinal bypass for obesity?

QUESTION: Please discuss the effectiveness of oral contraceptives in women who have undergone intestinal bypass surgery for obesity. Is there sufficient steroid absorption to prevent pregnancy? ANSWER: I am not aware of any data on the absorption of oral contraceptives in patients with an intestinal bypass. The effectiveness of oral contraceptives depends on the amount of estrogen and progestin administered, and decreasing the dosage to too low a level will increase the likelihood of pregnancy. Since the bypass will substantially reduce the absorptive area, it is quite possible that effective steroid absorption would not be obtained. In the absence of a study demonstrating adequate steroid absorption in this type of patient, in my opinion a contraceptive procedure other than oral contraceptives should be advised.

Contraceptive steroids and liver lesions.

Concern has been expressed about the possible untoward effect of oral contraceptives on the liver. During the past 10 yr an increasing number of cases of hepatic adenomas and related lesions has been reported in women using oral contraceptives. Such lesions occur only rarely, but it is the rarity itself that makes it difficult to evaluate the role of the contraceptive steroids. The enormity of the denominator in contraceptive steroid usage is so unwieldy that mechanisms to measure accurately the difference in an extremely small numerator are still plaguing the epidemiologist, who at best can supply only estimates. The data to date support an exceedingly low incidence of disease. This is much below the greater risks faced in accepted activities of daily living, particularly as affected by pregnancy itself. A plea is made to develop programs for better prospective evaluations of newer medications along with better animal experimental models.

Liver lesions and oral contraceptive steroids.

Two strains of mice, CF-LP and Swiss-Webster random-bred, were evaluated for liver neoplasia after administration of oral contraceptive steroids. No increased incidence of hepatocellular tumors was found beyond the variation expected by chance. The overall tumor incidence in treated and untreated groups was identical. No significant increase in tumor size was observed in the treated animals. Liver weights progressively increased in several of the treated groups. In both treated and untreated animals hepatocellular neoplasia was usually accompanied by intracytoplasmic inclusions similar to those observed in human liver tumors. Vascular lesions were observed in some of the animals receiving large doses of contraceptive steroids. While these may be the result of local toxicity, their similarity to lesions observed in benign liver tumors warrants further investigation. No evidence was found to suggest that contraceptive steroids act as initiators of liver neoplasia.