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Comparative Aspects of Contraceptive Steroids: Effects Observed In RatsConsulting Pathology Services, 12 Cherryville-Stanton Road, Flemington, New Jersey 08822 Current regulatory guidelines for testing contraceptive drugs in long-term rodent studies have established dosages based on multiples of the proposed human usage level. These multiples in rodents are 1–2, 10, and 50. The estrogen/progestogen ratio for most human contraceptive drugs ranges from 1/5 to 1/80. One of the biological endpoints in arriving at the human estrogen/progestogen ratio is the development of an endometrial decidualization response. The ratio necessary to achieve a similar uterine response in the rat is 1:10,000 to 1:20,000. Thus, dosages in the rodent, when based only on a multiple of the proposed human usage level, result in a highly estrogenic combination with estrogen being completely dominant. Continuously elevated estrogen in the rat is toxic to dopaminergic neurons in the hypothalamus which secrete prolactin inhibiting factor (PIF). Hyperplasia of pituitary lactotrophs occurs from both the direct stimulatory effect of estrogen and the uninhibited secretory activity of lactotrophs related to depressed PIF secretions. Prolactinomas result. Increased levels of prolactin lead to mammary gland stimulation and tumor development. Dosage levels for future rodent studies of contraceptive drugs should be based on pharmacokinetics, endocrine profiles, and biological endpoints rather than on multiples of the human usage level.
Key Words: Contraceptive safety studies • pituitary • mammary gland • estrogen • estrogen/progestogen ratio • dopaminergic neurons • hypothalamus • prolactin
Toxicologic Pathology, Vol. 17, No. 2,
385-388 (1989) |
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