The relevance of the pharmacologic properties of a progestational agent to its clinical effects as a combination oral contraceptive.
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Levonorgestrel (LNg) is known for its marked progestational/contraceptive activity. As shown in animal experiments, however, high doses of LNg are required to elicit an androgenic response; in contrast, considerably lower doses of LNg are required for antiovulatory (contraceptive) action. Thus, a large dose separation exists between androgenic and contraceptive activity. When LNg is combined with an estrogen, as in the contraceptive formulations, the androgenic response is attenuated or negated. The results of recent clinical trials have demonstrated that the androgenic activity of LNg is not expressed at contraceptive doses, particularly when LNg is combined with ethinyl estradiol (EE), as in the low-dose monophasic/triphasic formulations (monophasic [Nordette]: 150 mcg LNg/30 mcg EE; triphasic [Triphasil/Trinordiol]: six days, 50 mcg LNg/30 mcg EE; five days, 75 mcg LNg/40 mcg EE; ten days, 125 mcg LNg/30 mcg EE). Clinical evidence from several trials confirms that sex hormone-binding globulin levels are increased, plasma androgen levels are decreased, and acne is markedly improved with the use of Triphasil and Nordette, suggesting a non-androgenic profile. (+info)
Effects of combined estrogen and progestin administration on plasma lipoprotein metabolism in postmenopausal women.
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Treatment of postmenopausal women with low doses of estradiol-17 beta (1 mg/d) and dl-norgestrel (0.075 [corrected] mg/d) significantly reduced fasting serum levels of low density lipoprotein (LDL) cholesterol and lowered very low density lipoprotein (VLDL) triglycerides in four of five subjects. To explain these results, the kinetics of VLDL and LDL apolipoprotein (apo) B turnover were studied by injecting autologous 125I-labeled VLDL and 131I-labeled LDL into subjects before discontinuing long-term (4-yr) treatment with the estradiol-17 beta and dl-norgestrel and again 7 wk after stopping treatment. The 24% mean decrease in VLDL apo B pool size during treatment was associated with a significant increase in VLDL apo B fractional catabolic rate (15 +/- 1 vs. 11 +/- 1 pools/d), whereas production rate was similar to control (24 +/- 3 vs. 21 +/- 2 mg/kg per d). There was a significant 25% mean decrease in LDL apo B pool size (27 +/- 2 vs. 36 +/- 3 mg/kg) due to a significant decrease in total (8.3 +/- 0.3 vs. 11 +/- 1 mg/kg per d) and independent (3.3 +/- 0.5 vs. 6.6 +/- 0.8 mg/kg per d, P less than 0.05) LDL apo B production. Estradiol-17 beta together with dl-norgestrel lowered plasma VLDL by enhancing their clearance and LDL by reducing their production. (+info)
Contraceptive steroid effects on lipids and lipoproteins in cynomolgus monkeys.
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Seventy-three adult female cynomolgus monkeys fed an atherogenic diet were studied to determine the effect of two different combination contraceptive steroid preparations containing equivalent amounts of estrogen but different progestin components on plasma lipids and lipoproteins. Our hypothesis was that any high density lipoprotein (HDL) lowering effect of the contraceptive steroid preparations was proportional to the rise in total serum cholesterol caused by the progestins. For 2 years, one group (Ovral [Wyeth Laboratories], n = 23) received 75 micrograms norgestrel and 7.5 micrograms ethinyl estradiol daily, while another (Demulen [Searle & Co.], n = 25) received 150 micrograms ethynodiol diacetate and 7.5 micrograms ethinyl estradiol daily. The control group (n = 24) received no treatment. On average, the two oral contraceptive groups had higher total serum cholesterol and triglyceride concentrations but lower HDL cholesterol concentrations and smaller low density lipoproteins (LDL) compared with the control group. There was an inverse relationship between total serum cholesterol and HDL cholesterol for all three groups, but at any given total serum cholesterol concentration between 350 and 500 mg/dl, the Ovral group had HDL cholesterol concentrations that averaged 37% and 14% lower than the control and Demulen groups, respectively. The decrease in HDL concentrations with oral contraceptive treatment was associated with a sharp decrease in (HDL2b)gge protein (82% for Ovral and 59% for Demulen) and a corresponding increase in (HDL3b,c)gge protein as determined by gradient gel electrophoresis. Of 23 animals in the Ovral group, six had HDL subfractions greater than 10 nm diameter (HDL2b)gge compared with 22 of 24 animals in the control group. Although LDL size, on average, was smaller and plasma triglycerides were greater with oral contraceptive treatment compared with controls, there was no apparent relationship between LDL size and plasma triglyceride concentrations.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
Malignant neoplasms of decidual origin (deciduosarcomas) induced by estrogen-progestin-releasing intravaginal devices in rabbits.
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A combination of estrogen and levonorgestrel was continuously delivered to 23 adult rabbits for up to 2 years via a Silastic ring device sutured into the vagina. Twenty-one control rabbits were given similar rings devoid of drugs. A marked decidual reaction of the endometrium occurred in 16 of 23 test rabbits. In 14 test rabbits (61%) malignant tumors developed of decidual type cells not heretofore described. The deciduosarcomas were composed of anaplastic cells that invaded the uterine walls, uterine lymphatics, and in 4 of 13 (31%) rabbits that survived 2 years of treatment, the tumors metastasized to the lungs. Several deciduosarcomas appeared to arise within the spleen or other abdominal organs. Other drug-related lesions included uterine or vaginal polyps, endometrial atrophy, and focal necrosis and mineralization of the uterine wall. Cells from several deciduosarcomas failed to produce tumors in nude mice or to colonize on soft agar. No decidualization or decidual neoplasms were seen in the controls. (+info)
Influence of pregnancy, oophorectomy and contraceptive steroids on gall bladder concentrating function and hepatic bile flow in the cat.
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Pregnancy and contraceptive steroids are associated with a raised incidence of cholesterol gall stone disease. In pregnancy there is an increase in the size of the gall bladder. Investigation of hepatobiliary function in man and mammals has not established if the enlarged gall bladder is simply dilated, or if the absorptive capacity of the mucosa has changed. In the present study the concentrating function of the gall bladder and bile secretion from the liver were studied in pregnant animals, oophorectomised animals and animals treated for three months with contraceptive steroids. The effects of intravenous administration of prolactin, progesterone and oestrogen were studied in oophorectomised animals. It was found that the net rate of water absorption in the gall bladder of pregnant animals was doubled, while oophorectomy and contraceptive steroids did not affect this variable. The volume outflow of bile was enhanced in pregnant animals and in animals treated with contraceptive steroids. Intravenous infusions of prolactin, oestrogen or progesterone were found not to influence gall bladder concentrating function, nor hepatic bile secretion in oophorectomised animals. (+info)
Influence of 12-O-tetradecanoylphorbol-13-acetate on proliferation and maturation of human breast carcinoma cells (MCF-7): relationship to cell cycle events.
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Exposure of MCF-7 human mammary carcinoma cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) results in changes in cell morphology and arrest of cell growth. The inhibition of cell proliferation and the increase in cell volume are concentration dependent; these effects are reversible upon removal of the tumor promoting agent. Electron microscopic studies reveal that TPA increases endoplasmic reticulum and induces the appearance of secretory granules. MCF-7 cells treated by TPA therefore present morphological characteristics of secretory cells. These effects of TPA on MCF-7 cells are accompanied by specific disruption of cell cycle events, a block of cells in G1 at the expense of S base, and a delayed passage through G2. Studies in which a cell cycle lock in G1 is produced by tamoxifen show that exposure of such cells to PA produces cell morphological changes and an inability to progress through the cell cycle when estradiol is added. (+info)