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PubMed1992

FDA requirements for nonclinical testing of contraceptive steroids.

Written guidelines for the preclinical testing of contraceptive steroids have not been revised since 1968 despite the fact that many important changes have been implemented by the FDA's Division of Metabolism and Endocrine Drug Products. This paper describes the new preclinical testing requirements and the rationale for their implementation.

Animals↗
PubMed1991

Oxidative status and oral contraceptive. Its relevance to platelet abnormalities and cardiovascular risk.

Oral contraceptive (OC) use is a risk for thrombogenic events. This paper reviews effects of OC on oxidative status, coagulation, and platelet activity. Complicating effects of cardiovascular risk factors such as smoking, diabetes, hyperpidemia, and hypertension, are discussed. From these data we conclude that: 1. OC use modifies slightly but significantly the oxidative status in women and in animals by decreasing in plasma and blood cells the antioxidant defenses (vitamins and enzymes). 2. The changes in the oxidative status are related to an increase in plasma lipid peroxides apparently responsible for the hyperaggregability and possibly the imbalance in clotting factors associated with the OC-induced prethrombotic state. 3. These effects of OC appear to be increased by a high intake of polyunsaturated fat and counteracted by supplements of vitamin E. 4. The risk factors acting synergistically with OC, have all been shown to increase platelet reactivity. In addition, smoking, diabetes, and, to some extent, dyslipidemia are associated with an increased level of lipid peroxides and concomitant changes in the antioxidant defenses that can be additive to those induced by OC. Thus, free radicals and lipid peroxidation could be the underlying mechanism in the predisposition to thrombosis induced by most risk factors in OC users. 5. Results of epidemiologic and experimental studies in this field will be concordant only when diet and natural antioxidants will be systematically taken into consideration.

Animals↗
PubMed1979

High-dose medroxyprogesterone acetate (MPA) treatment in advanced breast cancer. A review.

Medroxyprogesterone acetate (MPA) when employed at high doses (greater than or equal to 500 greater than or equal to 1000 mg/day i.m.) can produce objective remission with improved survival in about 30% of postmenopausal women with advanced breast cancer resistant to cytotoxic drugs and endocrine therapies. When administered to women not previously treated with chemotherapy, the objective remission response rate reached 40%. From available evidence, high dose MPA can be considered a useful agent in the treatment of advanced breast cancer in postmenopausal women with soft tissue, pulmonary, pleural or osseous involvement even when patients have become refractory to prior hormone and cytotoxic therapies. Early results suggest that the response rate can be increased in patients with estrogen and/or progesterone-positive receptors. It is note worthy that in a study conducted on postmenopausal women resistant to cytotoxic and/or hormonal drugs, the median duration of survival was 13.5 months, while CRs plus PRs did not reach the median at 24 months after starting MPA treatment. High dose MPA is essentially devoid of major side effects. Relief of pain, increase in appetite and body weight, and sense of well being are characteristic features of the improved quality of life under MPA treatment. However, a gluteal abscess (from 2% to 20% dose related) is the most frequent side effect. A promising area for future studies is combined therapy using hormonal and cytotoxic agents or alternating sequential combinations. Well-designed studies are needed to develop means for increasing the complete response rate and therefore survival. Recent studies of combined chemo- and hormonal (MPA) therapy have yielded objective tumor regressions of 53 to 80% with an increased rate of complete remissions and duration of response.

Animals↗
PubMedDate not supplied

Pharmacological studies of a contraceptive drug anordrin.

A new oral contraceptive--Anordrin has been discovered. It is an A-Nor-steroid with some estrogenic activity and possessing a significant anti-fertility activity in mice, rats, rabbits, hamsters and dogs. In rats, AF-53, administrated repeatedly, led to sterility but did not alter mating behaviour, and the fertility of the animals recovered soon after cessation of the medication. In sub-minimal antifertility doses it has no teratogenic effect. Acute and chronic toxicity tests in animals showed that this drug did not cause any apparent abnormality in the blood picture, liver and renal functions, as well as in the histological examinations of organs. Experiments with 14C-labelled Anordrin showed that this drug could be absorbed rapidly but not completely in the gastrointestinal tract. The peak blood level was usually attained at 9 hours after administration. The drug excreted in the urine reached a maximum in 10--12 hours. Higher radio-activity was found in bile and gastrointestinal tract and was also excreted in large amounts in the feces. In clinical trials it is administrated only once post-coitally. The time for taking the drug is not limited by the menstrual cycle and it is unnecessary to be taken successively. Thus Anordrin is a convenient, safe and effective oral contraceptive drug.

Alkynes↗
PubMed1992

Contact factor proteases and the complexes formed with alpha 2-macroglobulin can interfere in protein C assays by cleaving amidolytic substrates.

Plasma from women taking combined oral contraceptives and cold-activated plasma contain proteases which cleave chromogenic substrates in protein C assays in the absence of protein C activators such as Protac. This spontaneous activity makes a background substraction necessary and makes protein C (PC) assays less accurate. We investigated two commonly used substrates < Glu-Pro-Arg-pNA (S-2366) and 2AcOH.H-D-Lys(Cbo)-Pro-Arg-pNA (PC substrate) and found that cold-activated normal and protein C-deficient plasmas gave absorbance values up to 300 times higher than buffer blanks. FXIa cleaves these substrates but activity was not blocked by corn or lima bean trypsin inhibitors, soy bean trypsin inhibitor (SBTI), hirudin or epsilon-amino-n-caproic acid (EACA). Kaolin activation of normal, FXI, FIX, FVIII, FVII and protein C-deficient, but not of FXII or prekallikrein (PKK)-deficient plasmas led to cleavage of chromogenic substrate for protein C. The protein C substrates were cleaved by purified kallikrein and alpha- and beta-FXIIa. Immunoabsorption with alpha 2-macroglobulin (alpha 2M) antibodies removed 60% of the alpha 2M and 70% of the activity on PC Substrate. Gel filtration of normal plasma on Sephadex G-150 gave a single peak of protein C activity and antigen in the included volume. After cold activation of the fractions, a second protein C-like peak appeared in the void volume, but with no detectable protein C antigen. This peak coincided with alpha 2M (chromogenic and ELISA) and plasma kallikrein (S-2302), but FXII (measured with a substrate insensitive to kallikrein) eluted separately.(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗
PubMed1979

Subdermal norethindrone pellets -- a method for contraception?

The mode of action of compressed pellets containing 85 per cent norethindrone (NET) and 15 per cent cholesterol was studied. Four pellets were inserted subcutaneously, in each of five healthy volunteers and left in place for 200--229 days. The NET content of the pellets varied between 23.9 mg and 25.6 mg; and the cholesterol content between 4.2 mg and 4.5 mg. Plasma levels of NET, estradiol and progesterone were determined by radioimmunoassays. Plasma levels of NET varied mostly between 1--2 ng/ml the first month after insertion. After two months plasma levels of NET ranged between 0.5 ng/ml and 1 ng/ml in all volunteers and there was a gradual decrease of the plasma NET levels throughout treatment. Pronounced day-to-day variations in plasma NET levels were recorded. The release rates of NET was calculated to be between 187 micrograms/day and 243 micrograms/day among the five volunteers. Ovulations occurred in four out of five subjects during treatment. This study indicates that the release of gestagen from four NET pellets was only initially high enough to completely inhibit ovulation and that to accomplish full contraceptive efficacy, a higher dose, i.e. more pellets, would have to be inserted.

Adult↗
PubMed1979

Pituitary and ovarian function in women receiving hormonal contraception.

A study was performed to further evaluate pituitary-ovarian function in women receiving an oral contraceptive preparation. Basal hormone levels (follicle stimulating hormone, luteinizing hormone, estradiol and prolactin) and gonadotropic response to gonadotropic releasing hormone were studied in 12 healthy, regularly ovulating women in the early follicular and mid-luteal phases of their menstrual cycle (non-treatment control period). These same women were then given NORDETTE (ethinyl estradiol 30 microgram +d-Norgestrel 150 microgram) cyclically for 3 months. In the third month of treatment, the tests were repeated on day 21, i.e. after 21 active pills, and on day 28, i.e. after 21 active and 7 inactive tablets. On active preparation, basal luteinizing hormone, follicle stimulating hormone and estradiol and gonadotropin response to gonadotropin releasing hormone were significantly suppressed. However, by day 28 (after completion of the inactive tablets), basal gonadotropin and estradiol concentrations and the gonadotropic response to gonadotropic releasing hormone were not significantly different to their pretreatment levels. No consistent change in prolactin concentration occurred as a result of oral contraceptive therapy. These results indicate that the 'active' component of even a relatively low-dose pill causes considerable suppression of pituitary-ovarian function but that after 7 days of placebo, pituitary function and basal estradiol secretion have virtually returned to normal.

Adolescent↗
PubMed1992

Effect of oral contraceptives on plasma beta-endorphin and corticotropin at rest and during exercise.

Concentrations of immunoreactive beta-endorphin and corticotropin in plasma were studied in 27 healthy physically active women at rest and after the exercise test on a treadmill requiring 60% and 90% of the maximal oxygen consumption. Eleven of the subjects were on a combination-type of oral contraceptive pills, and the remaining 16 did not use any pills. Plasma immunoreactive beta-endorphin levels at rest were higher in pill non-users than in pill users. Corticotropin levels at rest did not differ between the pill users and non-users. After the 60% exercise test a slight increase was found in the concentrations of corticotropin and beta-endorphin in the pill non-users but not in the pill users. In the 90% exercise test, plasma beta-endorphin and corticotropin levels increased significantly in both groups. We conclude that the use of oral contraceptives may elevate the threshold of the intensity of exercise required to increase beta-endorphin and corticotropin secretion. Decreased resting concentration of beta-endorphin in pill users can be explained by suppression of normal cyclic ovarian function.

Adrenocorticotropic Hormone↗
PubMed1991

Inhibition of antipyrine metabolism by low-dose contraceptives with gestodene and desogestrel.

To examine the effects of the two newest monophasic oral contraceptives on liver microsomal drug metabolism, plasma kinetics and urinary metabolite excretion of antipyrine, a model substrate for liver microsomes, were evaluated. Plasma lipid and lipoprotein levels, and in particular the high-density lipoprotein subfractions, were also monitored in view of their apparent regulation by a P450-dependent system. Ten healthy volunteers were treated with each contraceptive for a period of 3 months in a crossover trial. Both contraceptives significantly reduced antipyrine clearance by 34.6% (gestodene) and 43.3% (desogestrel) by impairing the oxidative metabolism, particularly to the 4-hydroxy and 3-hydroxymethyl metabolites, with little difference between the two associations. In addition, with both a comparable highly significant rise of plasma triglyceride levels, apolipoproteins A-I and A-II and the high-density lipoprotein-3 subfraction was observed. Treatment with these new monophasic contraceptives may reduce the metabolism of concomitantly given drugs undergoing oxidative transformations.

Adult↗
PubMed1992

Effect of Norplant implants on liver, lipid and carbohydrate metabolism.

In this study involving 100 women, the metabolic changes seen with Norplant use were evaluated. Besides a significant increase in serum bilirubin, there were no other changes in liver function to suggest possible hepatocellular dysfunction at the end of five years. Even the raised mean levels of bilirubin remained within the normal clinical range for the local population. As regards lipid metabolism, total triglycerides, cholesterol and LDL-cholesterol were decreased through the five years of Norplant use. The HDL-cholesterol showed a significant increase in the first year; it then decreased over the years to its preinsertion level at the end of five years. As a result, the HDL-cholesterol/Total cholesterol - HDL-cholesterol showed a significant increase in the first year and then decreased to almost its preinsertion value at the end of five years. The findings appear to indicate Norplant use not to be contributory to cardiovascular risk. The use of Norplant was not associated with any significant effect on carbohydrate metabolism.

Bilirubin↗
PubMed1992

Concentration of fat, protein, lactose and energy in milk of mothers using hormonal contraceptives.

Energy, protein, lactose and fat were studied in the milk of mothers who were using different types of contraceptives. One hundred and eleven mothers made up the following groups. C: control (barrier and natural methods, or sterilization), n = 22; combined pill: LDP (low dose pill (levonorgestrel 0.15 mg + ethinylestradiol 0.03 mg)), n = 12 and MDP (medium dose pill (levonorgestrel 0.25 mg + ethinylestradiol 0.05 mg)), n = 13; MP (minipill (norethindrone 0.35 mg)), n = 37; DMPA (injectable progesterone (depot medroxiprogesterone acetate 150 mg)), n = 17; and IUD (plastic or copper intrauterine device), n = 10. The mean stages of lactation were, respectively, 15, 17, 5, 9, 5 and 9 weeks. The mean duration of observation for the study groups ranged from 2 to 4 weeks. Milk samples were collected before and after initiation of treatment (mean = 20 days; range = 14-103 days). The stage of lactation and the interval of nursing before sampling were recorded so that statistical account could be taken of these uncontrollable sources of variability. When incorporated as covariates, they showed that no significant differences existed between the groups tested, either before or after treatment.

Adult↗
PubMed1991

Pharmacokinetics of levonorgestrel in 18 women after 1 month of treatment with a triphasic oral contraceptive.

A triphasic levonorgestrel (LNG)- and ethinylestradiol-containing oral contraceptive was administered to 18 women. Plasma samples were obtained throughout a treatment cycle just before drug administration and on the last treatment day (day 21), several plasma samples were collected from each individual up to 48 h postadministration. LNG was determined by radioimmunoassay in all plasma samples. In addition, the concentration of sex-hormone-binding globulin (SHBG) was determined in plasma samples collected from the same subjects during treatment, as well as during a pre- and a posttreatment cycle. During the treatment cycle, plasma levels of LNG determined just before drug administration increased and reached steady state at about day 16. This increase was due to an increased dose of LNG according to the triphasic dose regimen, a concomitantly ethinylestradiol-induced increase in SHBG and due to pharmacokinetic accumulation, since LNG had a terminal half-life of approximately 28.5 h and the dosing interval was 24 h. Steady-state levels and pharmacokinetic parameters of LNG determined on the last day of treatment were in good accordance with previously published results.

Adolescent↗