Granulosa-cell tumours induced in mice by progesterone.

Lipschütz, Alexander; Iglesias, R; Panasevich, V I; Salinas, Socorro

doi:10.1038/bjc.1967.13

Cited by 22 publications

(5 citation statements)

References 15 publications

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“…The U.S. Food and Drug Administration established specific guidelines for the conduct of toxicity studies with oral contraceptive agents, requiring long-term evaluation in dogs and monkeys (Berliner, 1974). There have been several reviews on the effects of estrogens (Kirschbaum, 1957;MCihlbock, 1960;Marois, 1964;Heywood and Wadsworth, 1980) and progestogens (Lipschutz et al, 1966(Lipschutz et al, , 1967 in animals. Further, the results of several chronic studies in rodents with various combinations of sex steroids have been reported (King and Lubansky, 1962;Drill, 1963;Rieche, 1967;Toth, 1963;McKinney et al, 1968;Great Britain Committee on Safety of Medicines, 1972).…”

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confidence: 99%

Ten‐year oral toxicity study with norlestrin in rhesus monkeys

Fitzgerald¹,

Iglesia²,

Goldenthal³

1982

Journal of Toxicology and Environmental Health

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The long term effects of the oral contraceptive, Norlestrin, were evaluated in sexually mature female rhesus (Macaca mulatta) monkeys over a 10 year period. Norlestrin, a combination of norethindrone acetate and ethinylestradiol (50:1) was given orally on a continuous cyclic regimen of 21 d of dosing followed by 7 d without treatment. Groups of 16 monkeys each received the drug at dose levels of 0.05, 0.51, and 2.55 mg/kg representing multiples of 1, 10, and 50 times the human dose, respectively. A comparable group of 16 animals remained untreated and served as controls. Selected clinical and laboratory parameters were monitored throughout the study and all animals were necropsied and evaluated for gross and histopathologic changes. All dose levels were well tolerated and survival was not affected. There were no consistent treatment-related alterations in coagulation or other clinical laboratory parameters. Ophthalmologically, macular pigmentary anomalies were observed in all groups. Treatment-associated pathologic findings, representing exaggerated pharmacological responses with superimposed senile changes, including ovarian and uterine atrophy and dilatation of acini and ducts in the mammary gland. Periodic vaginal cytologic examination and mammary gland palpation did not demonstrate drug related changes. A small number of neoplasms was seen in all groups and a granulosa cell carcinoma of the ovary occurred in a control animal. The benign tumors consisted of three cutaneous papillomas: one in a low dose and one in a high dose animal, a uterine leiomyoma in one high dose animal, and a pancreatic duct adenoma in one low dose animal. The results of this study indicate that Norlestrin had no significant toxic manifestations or tumorigenic potential when administered on a cyclic regimen to female rhesus monkeys at levels up to 50 times the human dose for ten yr.

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confidence: 99%

Ten‐year oral toxicity study with norlestrin in rhesus monkeys

Fitzgerald¹,

Iglesia²,

Goldenthal³

1982

Journal of Toxicology and Environmental Health

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“…A low incidence of uterine sarcomas was reported in mice after administra¬ tion of progesterone and norethindrone (Lipschutz et al 1967), and in some strains of the cervix and vagina (Gardner 1959).…”

Section: Pituitary Tumoursmentioning

confidence: 99%

The Use of Rodents for Studies of Toxicity in Contraceptive Research

Leonard¹

1974

Acta Endocrinologica

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After nearly two decades of clinical use of oral contraceptives, clinical studies have shown a few rare adverse reactions, including jaundice, venous thrombosis and pulmonary embolism, ischaemic cerebrovascular effects, hypertension, amenorrhoea, breakthrough bleeding, anxiety, depression, weight gain, and changes in libido. Preclinical studies in rodents dosed with oral contraceptives did not and would not be expected to reveal side effects of such low incidence. A carcinogenic effect can be produced in certain strains of mice and rats when oestrogens, progestogens and combinations of these hormones are given in high doses throughout their life span. The susceptibility to tumour induction by hormonal contraceptives is not consistent in different strains of mice and rats, and if there is little or no predictive value in rodents it is difficult to see how they can provide useful information of the potential carcinogenicity of any of these compounds in women. Ideally, carcinogenic testing of oral contraceptives should be conducted in animal species which have a similar metabolic disposition of the drugs and similar feedback mechanisms which control ovulation and menstruation to that of women: subhuman primates and guinea pigs possess some of these characteristics.Many previous studies indicate that carcinogenic tests in rodents have not been carried out in a very satisfactory manner.

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“…This study seems to support the contention that besides gonadotropin stimulation, other factors may be involved in GCT devel opment. A large number of PMSG-injected mice developed generalized lympho sarcoma, the mechanism of which remains unknown.Granulosa cell tumors (GCT) have been successfully induced in mice by various methods such as by X-irradiation [1], administration of carcino gens [3,5], progestational steroids [8][9][10] and ovarian intrasplenic trans plantation [4,6). Some methods of GCT induction in mice seem to have in common prolonged ovarian exposure to excessive amounts of endo genous gonadotropins [2,11,12], The present study was an attempt to induce GCT in female Balb-C mice by prolonged administration of exogenous gonadotropins.…”

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confidence: 99%

Attempted Induction of Granulosa Cell Tumor in Balb-C Mice by Gonadotropin Administration

Menczer¹,

Komarov²,

Shenboum³

et al. 1977

Gynecol Obstet Invest

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An attempt of granulosa cell tumor (GCT) induction by prolonged administration of exogenous pregnant mare’s serum gonadotropin (PMSG) to young, mature, and middle-aged Balb-C mice resulted mainly in stromal luteal cell proliferation. 48.9% of young mice, 64.5% of mature mice and 65% of middle-aged mice developed luteal cell proliferation. This effect seemed to be dependent on duration of treatment, mainly in young mice. Young mice injected for less than 6 months developed significantly less luteal cell proliferation than those injected for more lhan 6 months. Only 1 GCT was found. This study seems to support the contention that besides gonadotropin stimulation, other factors may be involved in GCT development. A large number of PMSG-injected mice developed generalized lymphosarcoma, the mechanism of which remains unknown.

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Granulosa-cell tumours induced in mice by progesterone.

Abstract: Images Fig. 16 Fig. 17 Fig. 18 Fig. 19 Figs. 5-8 Figs. 9-11 Figs. 12-15 Figs. 1-4

Cited by 22 publications

References 15 publications

Ten‐year oral toxicity study with norlestrin in rhesus monkeys

Ten‐year oral toxicity study with norlestrin in rhesus monkeys

The Use of Rodents for Studies of Toxicity in Contraceptive Research

Attempted Induction of Granulosa Cell Tumor in Balb-C Mice by Gonadotropin Administration

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