Systemic effects of oral contraceptives.
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Determinations by immunologic methods of histidine-rich glycoprotein (HRG) and plasminogen, were made in plasma samples collected during one normal or hormone induced cycle in 15 young, normal women and in 11 women using oral contraceptives with 30 micrograms ethinyl estradiol and 150 micrograms levo-norgestrel. The hormone group showed an increase in plasminogen level to about 150% of normal, while the concentration of HRG was decreased to about 75% of normal. This resulted in a considerable relative increase in the concentration of free plasminogen in the hormone group (calculated from the equilibrium: HRG . plasminogen in equilibrium HRG + plasminogen, using KD = 1.0 microM), representing a doubling of that in the normal group. Hence, more plasminogen is available for binding to fibrin and activation in the hormone group.
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As in the female, gametogenesis in the male is under the control of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Their suppression should inhibit spermatogenesis. If a non-androgenic substance is used to suppress gonadotrophins, androgens must be supplemented to maintain virility, potency and metabolic processes. To avoid administration of several substances, testosterone and its esters were used to develop a male antifertility agent. Although azoospermia can be induced in a high proportion of men with administration of testosterone esters alone, this effect is not uniform. Even frequent injections with testosterone enanthate at weekly intervals fail to inhibit spermatogenesis in all participants. Combinations of gestagenic compounds with testosterone esters show a somewhat better effect, but again azoospermia is only achieved in around 50% of participants. LHRH analogues, although considered by many to offer a realistic potential for male fertility regulation, have not been proven to be successful for this purpose so far. Animal studies in monkeys and preliminary clinical trials demonstrate that agonistic analogues of LHRH have to be given continuously by pump or implant to achieve a pronounced effect on spermatogenesis. But even under these provisions, results in clinical trials have been worse than effects achieved with testosterone/gestagen combinations. Whether new antagonistic compounds offer a better potential awaits clinical trials. Studies in non-human primates demonstrate that testosterone by itself can maintain and initiate spermatogenesis. Based on these findings one could postulate an attenuating effect of high serum androgen levels after supplementation with available testosterone esters. Trials of alternative androgenic substances with slow-release characteristics and without high serum levels after single injections, like 19-nortestosterone hexyloxyphenylpropionate (19NT-HPP), tend to support this theory. With slow-release testosterone preparations under development by the WHO and more advanced delivery systems for LHRH analogues it is not unreasonable to speculate that an effective endocrine antifertility agent for the male will become available.
In a Swedish multicenter study, a total number of 835 women completed a total of 6472 treatment cycles. Half of them were allotted at random to use the monophasic oral contraceptive Neovletta, also known as Microgynon 30 (30 micrograms ethinyl oestradiol + 150 micrograms levonorgestrel in each tablet). The second half was allotted to Trionetta, also known as Triquilar, Trigynon and Logynon (6 tablets with 30 micrograms ethinyl oestradiol + 50 micrograms levonorgestrel, 5 tablets with 40 micrograms ethinyl oestradiol + 75 micrograms levonorgestrel and 10 tablets with 30 micrograms ethinyl oestradiol + 125 micrograms levonorgestrel). The latter version was also present in a 28-day version containing in addition 7 "placebo" tablets to be used in the otherwise tablet-free interval. The contraceptive reliability was excellent although one pregnancy occurred in the three-phase version. It could be attributed to patient failure. In all aspects of bleeding control, the three-phasic pill proved to be superior to the reference monophasic preparation. The extreme low incidence of missed withdrawal bleeding and stability already during the first months of use are noteworthy features. For both preparations, continuation rate was at six months of use about 85% and at 12 months it was a similar figure. The most common reason for withdrawal was bleeding, about 5% each for both preparation. No serious side-effects were reported. The study clearly indicates that the three-phasic version is a major improvement in spite of a considerably decreased total dose of the gestagen.
Early chorionic activity was assessed in the premenstrual days by means of serum HCG beta-fraction. As control, a group of women with no contraceptive use was studied; early chorionic activity was detected in 31.8% of the cycles. In the group bearing an inert IUD the incidence was 20%, which did not differ from the control; while in the medicated IUD groups (Cu-IUD and LNG-IUD) the incidences were 4.8% and nil, respectively. Both medicated IUD groups showed a significant difference when compared with the control, as well as the inert IUD groups. The meaning of these findings, pointing out differences in the main mechanism of action between inert and medicated IUDs, is discussed.
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Between November 1981 and March 1983, data were collected to evaluate risk factors for benign breast lesions in a case-control study based on 288 women with histologically proven benign breast disease, admitted for biopsy to the Tumor Institute of Milan, and 285 age-matched controls. Questions were asked about menstrual and reproductive characteristics, marital status, education, history of various diseases, and lifetime use of oral contraceptives and other hormonal treatments. Nulliparity or low parity, late age at first birth, and late menopause were associated with an increased risk of benign breast disease. The elevated risk associated with late age at first birth was not accounted for by parity. Early age at menarche was associated with an increased risk, but the estimate was not statistically significant. The data do not suggest that the use of oral contraceptives or other female hormones (such as estrogen replacement therapy) is related to the risk of benign breast disease. Risk was apparently lower, however, among current and long-term oral contraceptive users. There was no evidence of a trend with reference to body mass index. The present data indicate a substantial agreement between the risk factors for (pathologically confirmed) benign and malignant breast disease, not only directly, by showing a relationship with parity, age at first birth, and age at menopause, but also indirectly, by failing to produce evidence that greater weight or the use of oral contraceptives has a protective effect.
A clinical trial was carried out in which Norigest (200 mg norethisterone oenanthate) was administered by intramuscular injection every 56 days into 383 women studied for 5,521 woman-months of use. No pregnancies occurred. Continuation rates at the end of one, two and three years were 76.6%, 63.7% and 33.8%. Only minor side-effects were recorded. After one year of use, 20.1% women had gained more than 2 kg in weight and 14.8% had lost more than 2 kg. There was marked disruption of the menstrual pattern and irregular bleeding was the major cause of discontinuation. In 38% of the injection intervals analysed, women were amenorrhoeic. Norigest proved an effective and acceptable method of fertility control.
Several studies have showed a significant increase of plasma beta-endorphin levels during the periovulatory days of the menstrual cycle. The aim of the present study was to investigate the origin of the periovulatory changes of plasma beta-endorphin, trying to discriminate between a possible ovarian and/or pituitary origin. Daily plasma beta-endorphin, luteinizing hormone (LH), and cortisol levels were measured from the 8th to the 20th day of the menstrual cycle in healthy normal-cycling women (10 cases) before and during dexamethasone (DEX; 6 cases) or estroprogestinic treatment with monophasic (5 cases) or triphasic (5 cases) pill. In the control menstrual cycle, during the preovulatory days, a significant increase of plasma beta-endorphin was found. While oral contraceptives abolished the midcycle increase of plasma beta-endorphin, the periovulatory plasma beta-endorphin peak was present during DEX treatment. Plasma cortisol levels did not show any significant change throughout the control menstrual cycle, while they were significantly lowered by the DEX administration and significantly increased during estroprogestinic treatment. These results suggest that the increase of plasma beta-endorphin during the periovulatory days is related to the ovulatory function, and suggest a possible ovarian origin.
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Metabolic activation of the ethynyl substituent of the contraceptive steroid norethindrone to cause the loss of hepatic cytochrome P-450 and the formation of green pigments has been compared in vivo and in vitro in rat, hamster, guinea pig, rabbit, mouse and hen and with marmoset and human liver microsomal preparations in vitro. In vivo green pigment accumulation in the liver 4 hr after the administration of norethindrone (100 mg/kg, i.p.) varied 60-fold between species. Male rat was the most active in this respect, the hen was the least active. The accumulation of green pigments in female rats was 27% that of male animals. This sex-dependent difference was not seen in male and female mice. Cytochrome P-450 destruction in vivo was also greatest in the male rat given norethindrone, whereas no loss was detected in the hen. In other species, however, the correlation between green pigment accumulation and cytochrome P-450 destruction was not particularly good. When liver microsomes were incubated with norethindrone and an NADPH generating system in vitro, the ranking order between species with respect to the initial rates of green pigment formation was similar to that based on the hepatic accumulation of these compounds found in vivo. Human liver microsomes showed initial rates of green pigment formation which were only 2% of that seen in the male rat. No destruction of human microsomal cytochrome P-450 caused by norethindrone could be detected. The HPLC elution profile of the green pigments produced in the liver following the administration of norethindrone differed between species. Hepatic microsomal preparations in contrast, at least with short incubation times, formed only one green pigment. Results suggest that further metabolism of either norethindrone or the green pigment, involving a cytosolic factor(s), results in the varied HPLC patterns seen in vivo.
Endometrial histology and the haematological indices were studied in women receiving 200 mg of norethisterone enanthate (NET-EN) at 60-day intervals for 24 months as a method of contraception. Significant elevations occurred in the haemoglobin concentration and red blood cell counts during one year of therapy, while eosinophil counts showed a transient increase at 4 months of trial. The changes in the haematological indices seem to be due to stimulation of the erythropoietic system by NET-EN and may also be attributable to diminished blood loss due to amenorrhoea during the course of therapy. The endometrial histology revealed proliferative glands at 2 months which turned quiescent at 6-12 months of NET-EN therapy. Long-term use of 18 months showed atrophic changes with few glands, narrow lumina and stromal oedema.
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