Comparative Aspects of Contraceptive Steroids—Effects Observed in Beagle Dogs

Abstract

The effects of oral contraceptives have been studied in the beagle bitch for periods up to 7 yr. High doses of these potent estrogen: progestogen (E:P) combinations have been shown to promote tumors in the mammary glands, smooth muscle of the tubular genitalia, and occasionally in the transitional epithelium of the neck/trigone area of the urinary bladder. The contraceptive formulations used in humans are balanced with an E:P ratio of about 1:5 to 1:80 to produce a desired decidual response in the uterus. The corresponding ratio for producing the decidual reaction in the dog is 1:1,000 to 1:3,000 with the result that the dog is grossly overdosed with estrogens when given the human formulation at the usual multiples of up to 25 times the human dose. Smooth muscle tumors of the tubular reproductive tract are common sequelae to estrogen overstimulation in the dog and are known to occur in other species, including the human. The dog also has major differences in hormonal control and sensitivity when compared to humans. Progestogens stimulate synthesis and release of growth hormone (GH) in dogs which in turn is the major stimulant (with progestogens) of mammary growth and tumors. Evidence is accumulating which indicates that most if not all progestogens can produce mammary tumors in the dog if given by the correct route and at high enough dosage. In contrast, GH in humans is not increased nor does it have any significant mammotrophic role. Mammary tumors in dogs related to oral contraceptives are now widely considered to be irrelevant as a model or predictor for human tumors. Transitional cell tumors in the urinary bladder seem to be a species specific phenomenon seen on occasion in the dog, but not in the rat, monkey, or human. The usual location in the neck/trigone area may be related to the embryologic origin of this portion of the bladder, which derives from tissues more closely related to the genital organs than does the rest of the bladder.

Keywords

Progestins estrogens long-term studies tumors mammary gland reproductive tract urinary bladder

References

1. Beier S , Dusterberg B , El Etreby MF , Elger W , Neumann F , and Nishino Y (1983). Toxicology of hormonal fertility-regulating agents. In: Endocrine Mechanisms in Fertility Regulation, G Benagiano and E Diczfalusy (eds). Raven Press, New York, NY, pp. 261–346.

2. Berliner VR (1974). U.S. Food and Drug Administration requirements for toxicity testing of contraceptive products. In: Pharmacological Models in Contraceptive Development–Animal Toxicity and Side-Effects in Man, MH Briggs and E Diczfalusy (eds). World Health Organization Research and Training Centre on Human Reproduction, Karolinska Institutet, Stockholm, Sweden, pp. 240–253.

3. Briggs M and Briggs M (1983). Oral contraceptives containing estrogen plus progestogen. In: Endocrine Mechanisms in Fertility Regulation, G Benagiano and E Diczfalusy (eds). Raven Press, New York, NY, pp. 17–48.

4. Briggs MH (1983). Progestogens: Toxicological studies in animal models. In: Progestogens in Therapy, G Benagiano et al (eds). Raven Press, New York, NY, pp. 73–95.

5. Cameron AM and Faulkin LJ (1971). Hyperplastic and inflammatory nodules in the canine mammary gland. JNCI 47: 1277–1283.

6. Demopoulos RI (1977). Benign lesions of the myometrium. In: Pathology of the Female Genital Tract, A Blaustein (ed). Springer-Verlag, New York, NY, pp. 299–321.

7. Dickey RP (1983). Managing contraceptive pill patients, 3rd ed. Creative Informatics, Durant, OK, pp. 184–191.

8. Drill VA (1974). Some metabolic actions and possible toxic effects of hormonal contraceptives in animals and man. In: Pharmacological Models in Contraceptive Development–Animal Toxicity and Side-Effects in Man, MH Briggs and E Diczfalusy (eds). World Health Organization Research and Training Centre on Human Reproduction, Karolinska Institutet, Stockholm, Sweden, pp. 169–202.

9. Drill VA (1979). Evaluation of the carcinogenic effects of estrogens, progestins and oral contraceptives on cervix, uterus and ovary of animals and man. Arch. Toxicol. Suppl. 2: 59–84.

10.

10. Dunning WF , Curtis MR , and Segaloff A (1953). Strain differences in response to estrone and the induction of mammary gland, adrenal and bladder cancer in rats. Cancer Res. 13: 147–152.

11.

11. El Etreby MF , Graf KJ , Beier S , Elger W , Gunzel P , and Neumann F (1979). Suitability of the beagle dog as a test model for the tumorigenic potential of contraceptive steroids “A Short Review.” Contraception 20: 237–256.

12.

12. El Etreby MF (1980). Comparative aspects of the influence of contraceptive steroids on tumorigenesis in the reproductive organs of experimental animals and man. In: Animal Models in Human Reproduction, M Serio and L Martini (eds). Raven Press, New York, NY, pp. 443–453.

13.

13. El Etreby MF, Beier S, and Gunzel P (1988). Comparative endocrine pharmacodynamics of contraceptive steroids. Presented at the Symposium on Improving the Safety Requirements for Contraceptive Steroids, Geneva, Feb. 2–5, 1987 (WHO). Cambridge University Press, Cambridge, to be published.

14.

14. Geil RG and Lamar JK (1977). FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey. J. Toxicol. Environ. Health 3: 179–193.

15.

15. Goyings LS , Sukolowski JH , Zimbelman RG , and Geng S (1977). Clinical, morphologic, and clinicopathologic findings in beagles treated for two years with melengestrol acetate. Am. J. Vet. Res. 38: 1923–1931.

16.

16. Guyton AC (1981). Textbook of Medical Physiology, 6th ed. W. B. Saunders Company, Philadelphia, PA, pp. 916–930.

17.

17. Heywood R (1980). The experimental toxicity of systemic fertility regulating agents in laboratory animals. In: Animal Models in Human Reproduction, M Serio and L Martini (eds). Raven Press, New York, NY, pp. 433–442.

18.

18. Heywood R (1986). Animal models: Their use and limitations in long-term safety evaluation of fertility-regulating agents. Hum. Reprod. 1: 397–399.

19.

19. Hill R (1972). Pre-clinical toxicity of steroid hormones: Recent experiences with estrogens and progestogens in the dog. In: Advances in Steroid Biochemistry and Pharmacology, Vol. 3, MH Briggs and GA Christie (eds). Academic Press, New York, NY, pp. 29–38.

20.

20. Hill R and Dumas K (1974). The use of dogs for studies of toxicity of contraceptive hormones. In: Pharmacological Models in Contraceptive Development–Animal Toxicity and Side-Effects in Man, MH Briggs and E Diczfalusy (eds). World Health Organization Research and Training Centre on Human Reproduction, Karolinska Institutet, Stockholm, Sweden, pp. 74–89.

21.

21. King NW (1978). The reproductive tract. In: Pathology of Laboratory Animals, K Benirschke , FM Garner , and TC Jones (eds). Springer-Verlag, New York, NY, pp. 509–574.

22.

22. Larsson H , Hakanson R , Mattsson H , RyBerg B , Sundler F , and Carlsson E (1988). Omeprazole: Its influence on gastric acid secretion, gastrin and ECL cells. Toxicol. Pathol. 16: 267–272.

23.

23. Larsson KS and Machin D (1988). Predictability of the safety of hormonal contraceptives from canine toxicological studies. Presented at the Symposium on Improving the Safety Requirements for Contraceptive Steroids, Geneva, Feb. 2–5, 1987 (WHO). Cambridge University Press, Cambridge, to be published.

24.

24. Lipschutz A and Vargas L Jr (1941). Structure and origin of uterine and extragenital fibroids induced experimentally in the guinea pig by prolonged administration of estrogens. Cancer Res. 1: 236–249.

25.

25. Marchant J (1977). Animal models for tumors of the ovary and uterus. In: Pathology of the Female Genital Tract, A Bloustein (ed). Springer-Verlag, New York, NY, pp. 797–821.

26.

26. Napalkov NP (1976). Tumors of the thyroid glands. In: Pathology of Tumors in Laboratory Animals, Vol. I–Tumors of the Rat Part 2, VS Turusov (ed). International Agency for Research on Cancer, Lyon, France, pp. 239–272.

27.

27. Nelson LW , Botta JA Jr , and Weikel JH Jr (1973). Estrogenic activity of norethindrone in the immature female beagle. Res. Commun. Chem. Pathol. Pharmacol. 5: 879–882.

28.

28. Nelson LW and Kelly WA (1976). Progestogen-related gross and microscopic changes in female beagles. Vet. Pathol. 13: 143–156.

29.

29. Nelson WO (1939). Atypical uterine growths produced by prolonged administration of estrogenic hormones. Endocrinology 24: 50–54.

30.

30. Patten BM (1964). Foundations of Embryology, 2nd ed. McGraw-Hill Book Company, New York, NY, pp. 495–597.

31.

31. Perman V and Schall WD (1983). Diseases of the red blood cells. In: Textbook of Veterinary Internal Medicine–Diseases of the Dog and Cat, 2nd ed., SJ Ettinger (ed). W. B. Saunders, Philadelphia, PA, pp. 1938–2000.

32.

32. Robbins SL and Cotran RS (1979). Pathologic Basis of Disease, 2nd ed. W. B. Saunders, Philadelphia, PA, pp. 1264–1277.

33.

33. Teske E (1986). Estrogen-induced bone marrow toxicity. In: Current Veterinary Therapy IX–Small Animal Practice, RW Kirk (ed). W. B. Saunders, Philadelphia, PA, pp. 495–498.

34.

34. Weikel JH Jr and Nelson LW (1977). Problems in evaluating chronic toxicity of contraceptive steroids in dogs. J. Toxicol. Environ. Health 3: 167–177.

35.

35. Zbinden G (1986). Pre-clinical evaluation of contraceptive steroids: Regulatory requirements and scientific expectations. Hum. Reprod. 6: 401–404.