Effect of Oral Contraceptives on the Mammary Glands of Rhesus Monkeys: A Preliminary Report

Va, Drill; Dp, Martin; Er, Hart; Rg, McConnell

doi:10.1093/jnci/52.5.1655

Cited by 15 publications

(3 citation statements)

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“…During the early years of oral contraceptive use in the United States, the concern over long‐term use of hormonal agents in healthy women led to long‐term studies of high dose oral contraceptive use (10 and 50 times the human dose) in monkeys (Tavassoli et al, 1988; McKenzie, 1989). These 7‐ to 10‐year studies were undertaken in the late 60s and early 70s; interim and final results have been reported by several investigators (Drill et al, 1974; Geil and Lamar, 1977; Drill and Golway, 1978; Drill, 1981; Fitzgerald et al, 1982; Tavassoli et al, 1988; Valerio, 1989).…”

Section: Effects Of Hormonal Agents On the Mammary Glandmentioning

confidence: 94%

Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors

Cline

2007

Birth Defects Research Pt B

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This review provides a summary of the normal biology, development, and morphology of the breast in nonhuman primates (macaques), and of the major published work addressing hormonally-induced changes in the breast of these animals. The mammary glands of macaques are anatomically, developmentally, and physiologically similar to the human breast, with similar expression of sex steroid receptors (estrogen receptors alpha and beta, progesterone receptor A and B, androgen receptors), estrogen dependent markers, and steroid metabolizing enzymes. Genetic similarity between human beings and macaques is high, varying from 95-99% depending on the sequence evaluated. Macaques develop hyperplastic and cancerous lesions of the breast spontaneously, which are similar in type and prevalence to those of human beings. They have a reproductive physiology typical of anthropoid primates, including a distinct menarche and menopause, and a 28-day menstrual cycle. These similarities give unique value to the macaque model for evaluation of the effectiveness and safety of hormonal agents. Such agents considered in this review include estrogens and progestogens, combined therapies such as oral contraceptives and post-menopausal hormone therapies, androgens, selective estrogen receptor modulators, phytoestrogens, prolactin, somatotropin, epidermal growth factor, and other novel agents with hormonal or growth factor-like activity. This review also includes a consideration of selected background changes and typical strategies and markers used for evaluation of experimentally-induced changes, including biopsy-based strategies designed to control for inter-individual variability and minimize numbers of animals used.

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Section: Effects Of Hormonal Agents On the Mammary Glandmentioning

confidence: 94%

Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors

Cline

2007

Birth Defects Research Pt B

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“…In other long-term studies, mammary cancer was not detected in rhesus monkeys given norethynodrel plus mestranol (Enovid-E), ethynodiol diacetate plus mestranol (Ovulen), or ethynodiol diacetate plus ethinyl estradiol (Demulen) over a 5-yr period (Drill et al, 1974;Drill and Golway, 1978). Similarly, studies with several progestin-estrogen combinations in monkeys have indicated little or no propensity of the compounds to induce nodules in the mammary gland (Geil and Lamar, 1977).…”

Section: Discussionmentioning

confidence: 96%

“…There have been only a few, mostly interim, reports of findings in chronic studies with oral contraceptives in monkeys (Kar et al, 1965;Drill et al, 1974;Drill and Golway, 1978;Geil and Lamar, 1977;Hill, 1978).…”

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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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Influence of oral contraceptives on breast diseases

Fechner¹

1977

Cancer

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Three sources of information are available pertaining to the effect of oral contraceptive hormones on the breast: 1) toxicity experiments in animals; 2) histologic examinations of breast tissue from women taking hormones; and 3) epidemiologic studies of women using hormones. Animals treated with hormones at doses equivalent to the human contraceptive level have not developed cancer of the breast at a greater than expected frequency. Monkeys, the one experimental animal with a reproductive cycle similar to humans, have not developed cancer during long-term hormone administration except for a single animal which likely represents a chance occurrence. In humans, histologic studies of breast tissue have failed to identify abnormalities which could be attributed to hormones with rare exceptions of secretory change indistinguishable from normal lactating breast. Epidemiologic studies have usually shown a decreased frequency of benign breast disease and neither an increase nor a decrease in carcinoma of the breast. The one exception to the latter statement is a possible increased risk of cancer in long-term users who have had previous surgery for benign breast disease.

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Effect of Oral Contraceptives on the Mammary Glands of Rhesus Monkeys: A Preliminary Report

Cited by 15 publications

References 0 publications

Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors

Assessing the mammary gland of nonhuman primates: effects of endogenous hormones and exogenous hormonal agents and growth factors

Ten‐year oral toxicity study with norlestrin in rhesus monkeys

Influence of oral contraceptives on breast diseases

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