Carcinogenic chemicals produce specific malignancies in a wide variety of animal species and in a high proportion of the treated animals. Oestrogens do not demonstrate a carcinogenic profile, producing malignancies in a limited number of animal species and in a low proportion of the treated animals. The effect of oestrogens depends on both species and strain.

A review of animal studies shows that the relationship of estrogens to the development of breast cancer in animals is strain- and species-dependent and that estrogens do not act as mammary carcinogens in animals. Similarly clinical evidence suggests that estrogens do not induce breast cancer in women. Hormone receptors refer to the specific site of action of chemicals (endogenous or exogenous). These chemicals produce a recognizable biological response. When carcinomas from estrogen-responsive organs contain estrogen-receptors the tumor is said to be estrogen-dependent. Tumors positive for estrogen receptors may respond to endocrine therapy. Hawkins et al. reported that on the average 54% (39-62%) of receptor positive breast tumors respond to endocrine therapy compared to only 6.8% (0-14%) response to receptor negative tumors. However high tumor levels of receptor activity do not necessarily mean that the tumor will respond to endocrine therapy; in addition an effective endocrine therapy does not cure the patient with a receptor positive tumor but rather acts to lower recurrence rates and hence prolong survival. Although estrogens may produce conditions favorable to breast tumor development the tumor may not be estrogen-induced. Pruitt et al. reported that hormone dependence may be observed in rat mammary adenocarcinomas induced by the administration of N-nitrosomethylurea (NMU). Ovariectomy and treatment with tamoxifen caused regression of NMU-induced tumors and prevented development of new tumors. The NMU data point out the possible effects of environmental chemicals on the occurrence of breast cancer. The effect or oral contraceptives (OCs) is also species-dependent as with estrogens; they do not have an overall carcinogenic effect in animals. Retrospective case-control studies cited in this chapter did not find a cancer risk in women who had used the pill for 2 or more years. In fact the studies by Spencer et al. and Vessey et al. suggest that women who had never used OCs have higher risks of breast cancer than pill users; such studies suggest that oral pills may actually have a protective effect against breast cancer.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

ABSTRACT Data on contraceptive steroids derived from properly conducted and interpreted animal studies can serve to predict effects that may be expected to occur in women. Important also is the absence of certain effects of the steroids in both animals and man. Since the drugs are for human use it is necessary that adequate clinical studies be conducted to confirm the predictions made regarding effectiveness and safety. Selected topics of importance are discussed to summarize our knowledge in specific areas and to illustrate correlations between the effects of contraceptive steroids in animals and in women.

A review of certain of oral contraceptives is presented. The areas selected for comment include: 1) endocrine 2) 3) thromboembolic disease 4) clotting factors and platelets 5) breast lesions and 6) metabolic related to thyroid and adrenal glands. There is a good correlation between the endocrine of progestins and oral contraceptives in laboratory animals and their actions in women. The use of controls is very important in studying effects. From the data supplied by many studies it is concluded that most of the side effects commonly associated with the oral contraceptives are not reactions to the medication. It has not been demonstrated that oral contraceptives cause thrombosis in animals or in women. During pregnancy and oral contraceptive use the blood level of clotting factors is increased but the incidence of thromboembolic disease is not. The platelet count remains normal in pregnant rats in human pregnancy and in animals and women on oral contraceptive therapy. Various studies conducted with oral contraceptives continue to demonstrate that the oral contraceptives used clinically do not have any adverse effect with regard to breast cancer in women. A discussion of metabolic limited to a review of data on oral contraceptives and adrenal and thyroid gland function and changes in the protein binding of cortisol and thyroxine seems to indicate further that the action of drugs in experimental animals can serve to predict which may be expected to occur in man.

The review of Clagett and Salzman discusses the prevention of venous thromboembolism in surgical patients and a recent letter comments that an additional prophylactic measure is to discontinue oral contraceptive before elective surgery in women of reproductive age. The comment is based on retrospective case-control studies and I wish to call attention to the report of Krauss and Breitner which does not demonstrate that the preoperative use of oral contraceptives represents a hazard to women undergoing surgery. In 6927 women not receiving oral contraceptives there were 26 cases (.38%) of postoperative pulmonary embolism; in 1225 who had received oral contraceptives for at least 3 months there was 1 case (.08%) of pulmonary embolism. The authors also note a lack of correlation between drug use and the severity of the embolism; among the women with emoblism there were 3 deaths all of which occurred in the group not using oral contraceptives. (FULL TEXT)

Studies in more than 70,000 women show no relation of the different doses of mestranol or ethinyl estradiol in oral contraceptives to the occurrence of superficial and deep-vein thromboembolic disease involving the lower extremities. The disease incidence did not differ significantly between the two estrogens or the different doses of the two estrogens employed in oral contraceptives, and no correspondence was seen between the dosage of estrogen and the incidence of disease. At all dosages of the estrogens, the incidence of thromboembolic disease was not greater than the average normal rate of 2.2 cases per 1,000 women of childbearing age per year.

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.