Comparative chronic toxicity of three oral estrogens in rats

Gibson, John P.; Newberne, James W.; Kuhn, W.L.; Elsea, J. R.

doi:10.1016/0041-008x(67)90050-6

Cited by 61 publications

(5 citation statements)

References 15 publications

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“…Estrogenic compounds do not induce LCTs in rats when given at doses that produce testicular atrophy, which can confound detection of LC hyperplasia (Gibson et al, 1967;Marselos and Tomatis, 1993;Schardein et al, 1970;Schardein, 1980). These earlier studies were also limited by small sample size and reduced survival.…”

Section: E Peroxisome Proliferatorsmentioning

confidence: 97%

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Cook

Klinefelter

Hardisty

et al. 1999

Critical Reviews in Toxicology

175

122

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Leydig cells (LCs) are the cells of the testis that have as their primary function the production of testosterone. LCs are a common target of compounds tested in rodent carcinogenicity bioassays. The number of reviews on Leydig cell tumors (LCTs) has increased in recent years because of its common occurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive reviews to identify all the compounds that have been shown to induce LCTs in rodents or has any review systematically evaluated the epidemiology data to determine whether humans were at increased risk for developing LCTs from exposure to these agents. This review attempts to fill these deficiencies in the literature by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, compounds that induce LC hyperplasia or tumors are enumerated, and the human relevance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typified by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dopamine receptors, androgen receptor antagonists, and inhibitors of 5alpha-reductase, testosterone biosynthesis, and aromatase. Most of these ultimately involve elevation in serum luteinizing hormone (LH) and/or LC responsiveness to LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growth factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-testis (HPT) axis of rats and humans are similar, such that compounds that either decrease testosterone or estradiol levels or their recognition will increase LH levels. Hence, compounds that induce LCTs in rats by disruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and prolactin receptors are either not expressed or are expressed at very low levels in the testes in humans, the induction of LCTs in rats by GnRH and dopamine agonists would appear not to be relevant to humans; however, the potential relevance to humans of the remaining five pathways of LCT induction cannot be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH levels; specifically, is the proliferative stimulus initiated by increased levels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantitatively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence includes the following: (1) the human incidence of LCTs is much lower than in rodents even when corrected for detection bias; (2) several ...

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Section: E Peroxisome Proliferatorsmentioning

confidence: 97%

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Cook

Klinefelter

Hardisty

et al. 1999

Critical Reviews in Toxicology

175

122

View full text Add to dashboard Cite

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“…Gibson et al (1967), measuring thyroid gland weight relative to body weight, did not find any distinct effect of oestrogen in the rat. In our studies in the rat oral contraceptives have been without effect or have decreased absolute thyroid weight, but body weight was also reduced; thyroid histology was normal.…”

Section: Metabolic Effectsmentioning

confidence: 72%

“…Oestrogens tend to increase both the absolute and relative adrenal weight in the rat, but with little evidence of cortical hyperplasia (Gibson et al 1967). The effects of oral contraceptives on adrenal weight vary considerably.…”

Section: Metabolic Effectsmentioning

confidence: 99%

Some Metabolic Actions and Possible Toxic Effects of Hormonal Contraceptives in Animals and Man

Drill¹

1974

Acta Endocrinologica

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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.The discovery and development of the first oral contraceptive by our labora¬ tories was the beginning of an extensive biological and clinical evaluation of these substances (Drill 1966). Indeed, the published papers available on oral contraceptives, oestrogens, progestins, and related articles on pregnancy, must now number in the thousands. Many of the publications are concerned with metabolic actions and possible side effects or toxic effects of the contraceptive steroids, but in the time allotted for my presentation this review must neces¬ sarily be limited to certain subjects. The areas of oral contraceptives selected * 4900 Searle Parkway, Skokie, 111., 60076.

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“…1). It is, however, difficult to correlate such a hypothesis with 3H-lndex 0 Normal livercells [3 I-GT positive (preneoplastic) liver cells the lack of PLLs in rats given the estrogens themselves, or if the estrogenic activity is so important, why non-steroidal estrogens also did not increase the incidence of PLLs (13). In this context it is interesting to note that 16a'pregnenolone-carbonitrile behaves as other sex steroids and increases proliferation of normal and putatively preneoplastic hepatocytes (Fig.…”

Section: Endocrine Activity Of Progesmgens In Ratsmentioning

confidence: 99%

Closing Remarks on the Symposium

King¹

1982

Toxicol Pathol

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In standard two year tumorigenicity studies some gestagens, alone or in combination with an estrogen have been shown to produce proliferative liver lesions (PLL) in rats. Estrogens in general have not produced PLLs; for ethinyl estradiol the situation is equivocal.The steroids which increase the incidence of PLLs have not been shown to have the characteristics usually associated with classical hepatocarcinogens such as diethylnitrosamine (e.g. negative mutagenicity and cytoxicity, failure t o bind covalently to DNA). Therefore, another mechanism must be assumed. A possible explanation is given by the ability demonstrated for a few steroids (mestranol alone or in combination with norethindrone, ethinylestradiol) to promote preneoplastic islands induced by diethylnitrosamine, resulting in an increase in tumor incidence over rats given only the carcinogen. Spontaneous preneoplastic islands in rats occur in various incidence in different strains and we have recently shown that their reaction to steroids-enhanced proliferation-is the same as the effect on preneoplastic islands produced by classical carcinogens. Sex steroids also enhance the growth or normal hepatocytes. It, therefore, seems reasonable to assume that sex steroids produce PLLs by acting on spontaneous preneoplastic lesions and not by the mechanisms usually associated with classical carcinogens.Extrapolating the incidence of PLLs in rats to a risk in humans may be highly misleading because of different pharmacokinetic patterns. Even in rats treated orally for two years with sex steroids dosed as multiples of the human contraceptive dose, resorption and biovailability may vary by a factor of 10 or more. It is, therefore, inappropriate t o state that one sex steroid is more active in the production of PLLs than another, unless the data from pharmacokinetic studies are taken into account.Available evidence shows that sex steroids act as tumor promotors and enhance the growth of normal hepatocytes. It is extremely doubtful whether a sex steroid producing PLLs in the rat after two years of oral treatment can be classified as an initiating tumorigen for the rat. Substantial risk for humans cannot be inferred, because of the high incidence of spontaneous preneoplastic lesions in rats, and because of the very high sensitivity of the rat liver t o a variety of chemically unrelated compounds including sex steroids.

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Comparative chronic toxicity of three oral estrogens in rats

Cited by 61 publications

References 15 publications

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Some Metabolic Actions and Possible Toxic Effects of Hormonal Contraceptives in Animals and Man

Closing Remarks on the Symposium

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