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Environmental Health Perspectives Apr 1983A number of different compounds, including phenobarbital, hypolipidemic drugs such as clofibrate and nafenopin, the sex steroids progesterone, cyproterone acetate,...
A number of different compounds, including phenobarbital, hypolipidemic drugs such as clofibrate and nafenopin, the sex steroids progesterone, cyproterone acetate, estradiol and mestranol, chlorinated hydrocarbons such as DDT, hexachlorocyclohexane, and TCDD and the antioxidant butylhydroxytoluene, appears to promote the development of liver tumors from previously induced initiated cells. The mechanisms of tumor promotion by several representative prototypes of these compounds were studied in rat liver in vivo. All liver tumor promoters mentioned above stimulate growth of normal liver. The growth response is due to cellular hypertrophy and/or increased rate of DNA (and cell) replication and/or decreased rate of cell death. Hepatocytes in foci or islands of altered cells (putatively preneoplastic) show higher rates of replication than normal liver cells; various different liver tumor promoters cause a further increase of proliferation of focal cells. The increased proliferative activity is found in different island phenotypes and thus seems to be a useful marker of the putative preneoplastic state. The focal cells respond to several factors limiting proliferation in normal liver, suggesting that they are not autonomous with respect to growth control. Early preneoplastic foci grow slowly without promotion, despite the relatively high rates of cell replication. Thus their cells seem to have a much shorter life-time than normal hepatocytes or to undergo reversion to the normal phenotype. Promoters seem to accelerate island enlargement by increasing cell replication and delaying cell death or remodeling. Thus, tumor promoters enhance the manifestation of the proliferation advantage of the putative initiated cell population. In addition, promoters cause increases in the number of detectable islands. This can partially be explained by enlargement of existing islands, but phenotypic changes that would enhance the probability of detection of remodelling islands and growth of dormant initiated cells, probably contribute to the apparent increase of island number. Putative preneoplastic foci of unknown origin are frequent in the liver of aged Wistar rats. They are morphologically and functionally very similar to those induced by carcinogens and are responsive to the mitogenic effect of tumor promoters. Promotion of these "spontaneous" foci may explain tumor appearance after long-term application of promoters.The findings may provide a basis for improved identification of initiated hepatocytes (and of initiating hepatocarcinogens) and for detection of tumor promoters. All suspected liver tumor promoters tested so far induced enhanced preneoplastic cell proliferation after single doses. The long-term carcinogenicity bioassay as currently performed does not discriminate between initiating and promoting properties of a test compound if the animals used develop spontaneous preneoplastic lesions in the organ affected.
Topics: Animals; Carcinogens; Cell Division; Female; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Precancerous Conditions; Rats; Time Factors
PubMed: 6873013
DOI: 10.1289/ehp.8350185 -
Health Services Reports 1972
Review
Topics: Animals; Breast Feeding; Chlormadinone Acetate; Contraceptives, Oral; Ethinyl Estradiol; Ethynodiol Diacetate; Female; Humans; Hydroxyprogesterones; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Intrauterine Devices; Lactation; Lynestrenol; Mestranol; Norethindrone; Norethynodrel; Pregnancy; Public Health
PubMed: 4120091
DOI: No ID Found -
British Journal of Cancer Jan 1992Data on 2,754 cases and 18,565 controls from a multinational hospital-based, case-control study were analysed to determine whether observed associations between combined... (Clinical Trial)
Clinical Trial Comparative Study
Data on 2,754 cases and 18,565 controls from a multinational hospital-based, case-control study were analysed to determine whether observed associations between combined oral contraceptives and breast cancer are similar for oral contraceptives with varying types and doses of oestrogens and progestins. After stratifying on duration of use, risk was found to be increased in current and recent users, and to decline with time since last use. These associations, of similar strength, were observed for users of products that contain mestranol and ethinyl estradiol, for women who used preparations with progestins derived from 19-nortestosterone and 17-alpha-hydroxyprogesterone, and for those who took preparations with relatively higher and lower doses of oestrogen. When products with equal doses of the same oestrogen or progestin and varying doses of the other hormonal constituent were considered, slightly higher relative risks per year of use were estimated for users of products with relatively higher than lower doses of either the constituent oestrogen or progestin, but the differences in relative risk could readily have occurred by chance. This study provides no evidence that risk of breast cancer in users of oral contraceptives varies by the type of oestrogen or progestin consumed.
Topics: Breast Neoplasms; Case-Control Studies; Contraceptives, Oral, Combined; Estrogens; Female; Humans; Progestins; Risk Factors; Time Factors; World Health Organization
PubMed: 1733433
DOI: 10.1038/bjc.1992.20 -
British Journal of Experimental... Dec 1976Male and female nonarteriosclerotic (virgin) and arteriosclerotic (breeder) Sprague-Dawley rats were subjected to acute myocardial infarction with isoprenaline. When... (Comparative Study)
Comparative Study
Male and female nonarteriosclerotic (virgin) and arteriosclerotic (breeder) Sprague-Dawley rats were subjected to acute myocardial infarction with isoprenaline. When myocardial necrosis was most intense, animals were given cortisone (high and low doses), Dianabol, or Enovid. Animals receiving large doses of cortisone manifested the best survival rate during the early stages of myocardial infarction. Although their serum enzyme levels were least elevated and their hearts showed tha least amount of damage, these animals had undergone the most intense body weight loss and began to die suddenly during the later stages of the experiment. These animals also manifested hyperlipidaemia, hyperglycaemia, septicaemia, severe disuse atrophy of their adrenal glands, and reduced Cmpd. B production. Animals treated with low doses of cortisone or with the anabolic and androgenic steroid, Dianabol, manifested none of the myocardial pretective effects of the larger dose of cortisone. These animals displayed a high incidence of left ventricular aneurysm formation concomitant with extensive cartilaginous metaplasia within the aneurysmal sites. Treatment with the contraceptive drug, Enovid, caused body weight loss, hyperlipidaemia, hyperglycaemia, gonadal atrophy and reduction of Cmpd. B production. Although the high dose of cortisone exercised definite salutary effects during early myocardial infarction, chronic treatment led to adrenal disuse atrophy and hypoadrenocorticism associated with sudden death during the later stages of myocardial repair. These findings indicate that proper adjustment of the dose and chronicity of corticosteroids used for treating the crisis of acute myocardial infarction must be made in order to provide effective protection against untoward pathophysiological conditions, acceleration of myocardial repair, but without suppression of adrenal function.
Topics: Adrenal Glands; Animals; Arteriosclerosis; Body Weight; Cortisone; Dose-Response Relationship, Drug; Drug Combinations; Female; Isoproterenol; Male; Mestranol; Methandrostenolone; Myocardial Infarction; Norethynodrel; Rats; Thymus Gland
PubMed: 1008997
DOI: No ID Found -
Japanese Journal of Cancer Research :... Jun 1992The present study reports the modulatory influences of combined oral contraceptive formulations, Ovral (0.05 mg ethinylestradiol plus 0.5 mg norgestrel per pill) and...
The present study reports the modulatory influences of combined oral contraceptive formulations, Ovral (0.05 mg ethinylestradiol plus 0.5 mg norgestrel per pill) and Noracycline (0.05 mg ethinylestradiol plus 0.1 mg lynestrenol per pill), on methylcholanthrene (MCA)-induced carcinogenesis in the uterine cervix of Swiss albino mouse. Placement of cotton thread impregnated with beeswax containing approximately 300 micrograms of MCA yielded cervical tumors in 0.0%, 8.6% and 26% animals, respectively, in 30, 60 and 90 days. Concomitant treatments with doses D1 (1/2000th of a pill), D2 (1/200th of a pill) and D3 (1/20th of a pill) of Ovral yielded cervical tumors in 0.0%, 0.0% and 4.5% mice at 30 days, 0.0%, 6.2% and 10% mice at 60 days and in 3.3% (P less than 0.05), 3.4% (P less than 0.05) and 47% mice at 90 days, respectively. Likewise, concomitant treatments with doses D1 (1/2000th of a pill), D2 (1/200th of a pill) and D3 (1/20th of a pill) of Noracycline yielded cervical tumors in 0.0%, 0.0%, 16.6% mice at 30 days, 4%, 3.7% and 54% (P less than 0.05) mice at 60 days and 3.2% (P less than 0.05), 20% and 63% (P less than 0.05) of mice at 90 days, respectively. Both Ovral and Noracycline displayed biphasic action on MCA-induced cervical carcinogenesis in mice. At lower dose levels (D1 and D2), they were inhibitory while at the higher dose level (D3) they were augmentatory in their actions. Both pills also significantly enhanced the incidence of cervical hyperplasia.
Topics: Animals; Body Weight; Carcinoma, Squamous Cell; Contraceptives, Oral, Combined; Contraceptives, Oral, Synthetic; Dose-Response Relationship, Drug; Drug Combinations; Ethinyl Estradiol; Ethinyl Estradiol-Norgestrel Combination; Female; Lynestrenol; Mestranol; Methylcholanthrene; Mice; Norgestrel; Precancerous Conditions; Uterine Cervical Diseases; Uterine Cervical Neoplasms
PubMed: 1644661
DOI: 10.1111/j.1349-7006.1992.tb00128.x -
Transactions of the American... 1970
Topics: Body Fluids; Body Water; Circadian Rhythm; Contact Lenses; Contraceptives, Oral; Cornea; Eye Diseases; Female; Humans; Menstruation; Pregnancy; Tonometry, Ocular; Water
PubMed: 5524214
DOI: No ID Found -
The Western Journal of Medicine Jan 1975
Review
Topics: Adolescent; Adult; Cerebrovascular Disorders; Contraceptives, Oral; Diethylstilbestrol; Estrogens; Female; Humans; Intracranial Embolism and Thrombosis; Male; Mestranol; Myocardial Infarction; Norethynodrel; Pregnancy; Prostatic Neoplasms; Pulmonary Embolism; Recurrence; Retrospective Studies; Thromboembolism; Thrombophlebitis; United Kingdom
PubMed: 1089003
DOI: No ID Found -
International Journal of Women's Health Aug 2010To review milestones in development of oral contraceptive pills since their introduction in the US 50 years ago in order to better understand how a new formulation with...
AIM
To review milestones in development of oral contraceptive pills since their introduction in the US 50 years ago in order to better understand how a new formulation with low-dose estrogen in an extended-cycle pattern fits into the evolution of birth control pills.
METHODS
This is a review of trends in the development of various birth controls pills and includes data from phase III clinical trials for this new formulation.
RESULTS
The first birth control pill was a very high-dose monophasic formulation with the prodrug estrogen mestranol and a first-generation progestin. Over the decades, the doses of hormones have been markedly reduced, and a new estrogen and several different progestins were developed and used in different dosing patterns. The final element to undergo change was the 7-day pill-free interval. Many of these same changes have been made in the development of extended-cycle pill formulation.
CONCLUSION
The newest extended-cycle oral contraceptive formulation with 84 active pills, each containing 20 μg ethinyl estradiol and 100 μg levonorgestrel, represents an important evolution in birth control that incorporates lower doses of estrogen (to reduce side effects and possibly reduce risk of thrombosis), fewer scheduled bleeding episodes (to meet women's desires for fewer and shorter menses) and the use of low-dose estrogen in place of placebo pills (to reduce the number of days of unscheduled spotting and bleeding). Hopefully, this unique formation will motivate women to be more successful contraceptors.
PubMed: 21072303
DOI: 10.2147/ijwh.s4886 -
Journal of Clinical Pathology Mar 196619-nor steroids in high and medium dosage in continuous or cyclic combined regimens with oestrogen produce an endometrium characterized by hyperinvoluted glands, a...
19-nor steroids in high and medium dosage in continuous or cyclic combined regimens with oestrogen produce an endometrium characterized by hyperinvoluted glands, a prominent predecidual reaction, suppressed arterioles, and dilated venules. When daily dosage is decreased to 2.0 mg. or less, the endometrium is composed of hyperinvoluted glands in an inert stroma; predecidual reactions are weak and infrequent; venules are rarely dilated, but spiral arterioles are suppressed.17-alpha-Acetoxyprogesterone derivatives in high and medium dosage given in a cyclic combined regimen with oestrogen produce similar but less intense effects to the 19-nor steroids. When given in cyclic sequential regimen, they produce an early secretory endometrium closely resembling normal patterns, chronologically retarded by about five days; in some instances a regressing, undatable secretory pattern is found, but predecidual response is minimal, and dilated venules are not seen.19-nor steroids in medium dosage given for 20 days without added oestrogen produce a late secretory endometrium with unpredictable variation from patient to patient and even from site to site within the same endometrium. Inhibition of the development of spiral arterioles is a common denominator in all progestagenoestrogen regimens. Modification of this element within the target tissue may be decisive for the morphogenesis of later vascular and stromal changes. Using synthetic progestagen-oestrogen regimens, endometrial gland secretion appears only after progestagen, whether given ab initio concomitantly with oestrogen or begun after a phase of oestrogen priming. Secretory vacuoles become evident about four to five days after progestagen is administered. The role of progestagen in secretion is interpreted as an indirect effect whereas its role in the development of decidual-like changes is construed as direct.
Topics: Biopsy; Endometriosis; Endometrium; Estrogens; Ethynodiol Diacetate; Female; Humans; In Vitro Techniques; Medroxyprogesterone; Mestranol; Norethynodrel; Ovulation; Progesterone
PubMed: 5909695
DOI: 10.1136/jcp.19.2.138 -
Cervical mucorrhea and spinnbarkeit in patients taking norethindrone plus mestranol (Norinyl 1-mg.).Fertility and Sterility 1968
Clinical Trial
Topics: Cervix Mucus; Clinical Trials as Topic; Drug Synergism; Female; Humans; Infertility, Female; Menstruation; Mestranol; Microscopy, Phase-Contrast; Norethindrone; Ovulation
PubMed: 4869631
DOI: 10.1016/s0015-0282(16)36669-9