Increased Serum Alkaline Phosphatase Induced by Dt-5061, an Oral Contraceptive, in Rats

Ohno, Hiroshi; Tojo, Hiroko; Kajimura, Tetuyo; Nomura, Mamoru

doi:10.2131/jts.19.supplementiii_507

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“…The marked increase in liver weights of treated females reflected the known co-mitogenic properties of estrogens in rat liver (Ni and Yager 1994). Elevated plasma levels of alkaline phosphatase in ethinylestradiol-treated rats have been shown to originate both from bone and liver, the rise of the liver-derived isoenzyme preceding and accompanying the cholestasis induced by this compound (Ohno et al 1994). However, histologically, no changes in the liver of treated animals were detectable in this investigation.…”

Section: Discussionmentioning

confidence: 95%

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et al. 2002

Archives of Toxicology

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Groups of five male and female Wistar rats were treated by gavage with 0, 0.01, 0.05 or 0.2 mg/kg body weight of the known synthetic estrogen ethinylestradiol for 28-32 days according to a modified enhanced OECD Test Guideline no. 407 in order to investigate which of the current and/or additional parameters would detect effects on the endocrine system reliably and sensitively and to provide data on intra-laboratory variability. Two identical studies (A and B) were run concurrently. The modified enhanced protocol requests the additional determination of triiodothyronine, thyroxine and thyroid-stimulating hormone (TSH), of the stage of the estrous cycle to ensure necropsy of all females in diestrus, of the number and morphology of cauda epididymal spermatozoa, and of additional organ weights (ovaries, uterus, thyroid, and male accessory reproductive organs), and histopathology of additional organs (pituitary, epididymides, coagulation glands, pancreas, and vagina). There were no treatment-related mortalities, clinical signs or changes in behavioral parameters. In male rats, 0.2 mg/kg was the maximum tolerated dose (MTD) resulting in reduced body weight gain. The only treatment-related alteration in hematological parameter was prolonged blood clotting time in high-dose females of both studies. Changes in clinical chemistry observed in study A were elevated alkaline phosphatase activity (high-dose females) and triglyceride levels (mid- and high-dose females and high-dose males). Changes in thyroid hormones and TSH of treated animals showed high variability with no clear dose-dependency, and could not be clearly related to estrogenic activity. In accordance to a suppression of the hypothalamic-pituitary-gonadal axis, decreased relative organ weights of the male accessory reproductive organs were obtained in both studies at the high dose. Corresponding histological changes were degeneration of the testicular germinal epithelium and atrophy of Leydig cells and of all accessory sex glands. Atrophy of the coagulating gland (study A) and seminal vesicles (study B) was also seen at 0.05 mg/kg. A marked increase in relative adrenal weight in male rats, accompanied by decreased vacuolization of zona fasciculata cells observed in both studies at the high dose seems to reflect an activation of the hypothalamic-pituitary-adrenal axis. The male mammary gland was sensitively affected. Increased numbers of small basophilic over large acidophilic cells indicated an estrogen-mediated feminisation and were detected at the low (study A) or mid dose (study B). Co-mitogenic properties of estrogens in rat liver were reflected by increased relative liver weights in females at the mid and high dose of study A and also at the high dose in study B. No treatment-related changes in endocrine organ weights were observed in treated females. Histological changes in the ovaries were increased numbers of apoptotic corpora lutea (from mid dose, study B) and of early stage follicles at the high dose in both studies. Classical direct estrogenic effects...

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Section: Discussionmentioning

confidence: 95%