Experimental Conditions Under Which Contraceptive Steroids May Become Toxic

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

doi:10.1038/212686a0

Cited by 22 publications

(7 citation statements)

References 7 publications

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“…The effects on the uteri of progesterone implanted for a month or longer were not correlated with rates of absorption, but were the reaction to the abolition of normal cyclic changes. The uteri increased in weight, sometimes to a patho¬ logical extent, and appeared to be over-stimulated by oestrogens, recalling those in oestrogen-treated guinea-pigs described by Lipschutz (1950) and others. The implanted progesterone does not protect against these changes, as might have been expected, perhaps because, in the non-pregnant female, progesterone never reaches a high concentration in the blood plasma (Heap & Deanesly, 1967).…”

Section: Discussionsupporting

confidence: 61%

“…The experiments were completed when references to somewhat similar findings in other species were seen in the literature. Lipschutz, Iglesias, Salinas & Panasevich (1966) observed increase in uterine weight, endometriosis and cystic glands in mice receiving progesterone over 13 months and in six out of twenty-four mice receiving 5-5 µg norethinodrel daily for 18 months. For inhibiting ovulation in mice 30 /tg daily of progesterone will suffice; on a body-weight basis this would correspond to 0-6 mg in a guinea-pig.…”

Section: Discussionmentioning

confidence: 77%

“…Some of the uteri were distended with fluid. There was a general resemblance to the uteri of the guinea-pigs which received continuous low oestrogen dosage, described and illustrated by Lipschutz and his colleagues (Lipschutz, 1950). Earlier Nelson (1936) had described fibroblastic proliferation in guinea-pig uteri after long-term treatment with oestrogens.…”

Section: Effects On the Uterusmentioning

confidence: 89%

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The Effects of Progesterone, Testosterone and Ergocornine on Non-Pregnant and Pregnant Guinea-Pigs

Deanesly¹

1968

Reproduction

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In guinea-pigs absorbing 0\m=.\1 mg or more progesterone daily from solid, subcutaneous tablets, follicles grow and regress normally as do existing corpora lutea, but ovulation is completely inhibited. The uterus, in the absence of cyclic changes, is continuously stimulated by ovarian oestrogens in progesterone-treated animals. It enlarges, sometimes becoming enormous, and shows various pathological changes.These are absent from the uteri of ovariectomized animals treated with progesterone. Five males which absorbed 0\m=.\26to 1\m=.\7 mg progesterone daily for 30 to 64 days had normal reproductive organs.Testosterone propionate, similarly administered, also inhibits ovulation; additionally it leads to a reduction in follicle growth and ovary size. Both steroids showed steady, slow rates of absorption as determined from tablet weights before and after implantation.Ergocornine, which is said to inhibit corpus luteum secretion in rats, had no such effect on corpora lutea in non-pregnant and pregnant guinea-pigs, when injected in solution. 272Ruth Deanesly Bouin's fluid and sectioned serially at 7 µ. Uteri were weighed after fixation and transfer to 70% alcohol. The ergocornine methane sulphate was dissolved in 20% alcohol and injected subcutaneously. Absorption from the progesterone tablets, weights up to 50 mg, proceeded slowly at a steady, fairly uniform rate (Tables 1, 2 and unpublished data) ; tablets remained solid and could be cleaned and re-used with similar results.Rates of absorption varied with the initial size and number of the tablets implanted. Plasma progesterone levels remained low in all progesterone treated, non-pregnant, normal or ovariectomized animals whose blood was examined. These levels, 2 to 3 ng/ml, were generally in the lower range of those recorded for non-pregnant guinea-pigs (1 to 13 ng/ml) by Heap, Perry & Rowlands (1967), but in ovariectomized animals with large amounts of progesterone (Table 2) they showed an appreciable rise, up to 25 ng/ml (Heap & Deanesly, 1967).

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 77%

Section: Effects On the Uterusmentioning

confidence: 89%

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The Effects of Progesterone, Testosterone and Ergocornine on Non-Pregnant and Pregnant Guinea-Pigs

Deanesly¹

1968

Reproduction

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“…Sarcoma induced by P and norethindrone in the endometrial stroma A tumour of spindle-shaped cells appeared in the endometrial stroma in 1 out of 32 animals receiving during 13 months 117 to 900 ,ug./day of P (Lipschutz, Iglesias, Panasevich and Salinas, 1966). This animal received 665 ,ug./day of P. Subsequently similar tumours were found in 15 out of the 142 animals having been treated during 18 months with P and having absorbed 18 to 900 ,ug./day (Table II).…”

Section: Endometriosis Of Cystic Glandsmentioning

confidence: 99%

Pathological changes induced in the uterus of mice with the prolonged administration of progesterone and 19-nor-contraceptives.

A¹,

Iglesias²,

Panasevich³

et al. 1967

Br J Cancer

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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).…”

Section: Please Scroll Down For Articlementioning

confidence: 97%

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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Experimental Conditions Under Which Contraceptive Steroids May Become Toxic

Cited by 22 publications

References 7 publications

The Effects of Progesterone, Testosterone and Ergocornine on Non-Pregnant and Pregnant Guinea-Pigs

The Effects of Progesterone, Testosterone and Ergocornine on Non-Pregnant and Pregnant Guinea-Pigs

Pathological changes induced in the uterus of mice with the prolonged administration of progesterone and 19-nor-contraceptives.

Ten‐year oral toxicity study with norlestrin in rhesus monkeys

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