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Two problems in oral contraception: arteriosclerotic cardiopathy and drug interactions.

The Authors examine two aspects of oral contraception: the risk of arteriosclerotic cardiopathy and the interaction with other drugs. The former is rather limited but increases significantly when other arteriosclerotic risk factors, first and foremost smoke, are present. The dose of both the estrogenic and the progestinic components also influences the risk. The Authors examine the most recent information on the interference of some drugs with the contraceptive effectiveness of synthetic, especially low-dose, estroprogestinics, which is mediated by changes of the intestinal absorption or metabolic clearance rate. Finally, they analyse the interference of contraceptive steroids with the kinetics of other drugs and, consequently, with the intensity of therapeutical and side effects.

Contraceptives, Oral↗

Thrombin-induced platelet malondialdehyde (MDA) formation in normal subjects and in women taking oral contraceptives.

Thrombin-induced platelet malondialdehyde (MDA) production and platelet count were studied in 82 male and 74 female healthy blood donors. 37 women on oral contraceptives (OC) had significantly lower values of MDA production than women who were not using the pill. There were no statistically significant differences of MDA production in women on a low dose estrogen, a medium dose, and a relatively high dose. Males had significantly higher values than females. In 15 further subjects (5 males, 5 OC-users, 5 OC-nonusers) the kinetics of MDA formation was determined by using increasing doses of thrombin. No significant differences could be found. Platelet count in women on OCs was lightly increased, but the difference was not significant.

Blood Platelets↗

Two oral contraceptives, efficacy, serum proteins, and lipid metabolism. A comparative multicentre study on a triphasic and a fixed dose combination.

A triphasic, combined oral contraceptive containing 30 - 40 - 30 micrograms ethinyloestradiol (EE), and 50 - 75 - 125 micrograms levonorgestrel was compared with a fixed dose combination containing 30 micrograms EE and 150 micrograms desogestrel in a randomized multicentre trial in 193/199 women and 1 063/1 073 cycles, respectively. The duration of the trial was six months. Eleven centres in Denmark, Sweden, and Norway participated. Contraceptive reliability, bleeding control and side effects were evaluated. Influence on serum sex hormone binding globulin (SHBG) and transcortin was assayed as well as lipid metabolism. Three pregnancies occurred in the group using the triphasic regimen but none in the fixed dose regimen. Two of the three pregnancies were considered drug failures and the third a possible interaction. Possible reasons for the triphasic contraceptive failure are discussed with special reference to a British report on eight pregnancies. Bleeding control appeared to be equally good for the two preparations. However, the number of cycles with spotting, breakthrough bleeding and missed withdrawal bleeding were above the levels reported earlier on the triphasic regimen. About 80 per cent of the women completed the planned six months on either combination. Side effects were generally mild and in accordance with earlier reports on low dose oral contraceptives. Metabolically the triphasic levonorgestrel combination increased SHBG 100 per cent versus 200 per cent for the fixed desogestrel combination. Transcortin rose about 98 and 110 per cent, respectively. Both preparations induced similar changes in the levels of lipids and lipoproteins with the exception of a significant increase in the arachidonic content of cholesterol during treatment with the desogestrel-containing preparation.

Adolescent↗

Cutaneous malignant melanoma in women: exogenous sex hormones and reproductive factors.

The roles of exogenous sex hormones and reproductive factors in the causation of malignant melanoma of the skin in women were examined in a case-control study of 276 patients and 276 matched controls in Western Australia. There was no consistent evidence of a relationship between the incidence rates of different histogenetic types of melanoma and age at menarche, duration of menstrual life, degree of obesity, number of pregnancies more than 20 weeks in duration or use of oral contraceptive preparations (OCP). Exposure to OCP was examined separately for different age periods and in different intervals of time before diagnosis; no consistent trend emerged. There was borderline evidence of an association of superficial spreading melanoma with duration of use of unopposed oestrogens. On the basis of seven studies of the relationship of melanoma to OCP published to date, we estimate that the total incidence rate of melanoma in OCP ever-users is unlikely to be increased by more than one third the rate in never-users.

Adolescent↗

Effect of depo-medroxyprogesterone acetate on serum progesterone levels when administered on various cycle days.

Depo-medroxyprogesterone acetate (DMPA) in the conventional dose of 150 mg, was administered intramuscularly to 49 healthy, already sterilized, Thai women on cycle day 5 (13 subjects), day 7 (12 subjects), day 9 (13 subjects) and day 11 (11 subjects) of normal menstrual cycles. Serum progesterone levels were then monitored in order to ascertain the latest follicular phase day in the cycle (up to day 11) when ovulation would be inhibited in the first month after injection. Among the 25 subjects who received DMPA on day 5 and 7, no longitudinal serum progesterone level rises indicative of ovulation were detected. When DMPA was given on day 9 and 11, 2 out of 13 subjects (15.39%) and 3 out of 11 subjects (27.28%), respectively, had serum progesterone levels characteristic of ovulation. It is concluded that the initial cycle's ovulation can also be inhibited when DMPA is administered on day 7 of that cycle. However, DMPA administered on day 9 and 11 failed to inhibit ovulation of that cycle in some of the subjects.

Adult↗

Blood prolactin levels: influence of age, menstrual cycle and oral contraceptives.

The relationships between the serum levels of estradiol, progesterone and prolactin have been analysed in normal women in relation to age, to menstrual cycle, and in oral contraceptives users. We have been able to detect significant differences between the prolactinemia values during the cycle in different age groups as well as following oral contraceptives. A word of caution is presented for the evaluation of the prolactin blood level which should always be related to the physiological phase of the cycle and to the age of the subjects.

Adolescent↗

Progesterone receptor blockage. Effect on uterine contractility and early pregnancy.

RU 486 is an antiprogestin which acts at the receptor level. In the present study the effect of this compound on uterine contractility and sensitivity during early pregnancy was evaluated in 10 patients. Five patients in the 6th to 7th week of pregnancy received 25 mg RU 486 twice daily for four days. On the fourth day of treatment, uterine contractility was recorded. The remaining five early pregnant patients were untreated and served as control. Withdrawal of progesterone locally by RU 486 treatment resulted in the development of a regular uterine activity which was in sharp contrast to the low level contractility pattern found in the untreated control patients. Also the sensitivity to prostaglandin increased following RU 486 treatment. The efficacy of a sequential therapy of RU 486 and the PGE analogue 16-phenoxy-tetranor-PGE2 methyl sulfonylamide for termination of early pregnancy was also studied. Thirty-four early pregnant women (duration of amenorrhea for up to 49 days) admitted to the hospital for termination of their pregnancy volunteered for the study. The patients received 25 mg RU 486 twice or four times daily for four days. In the morning of the fourth day of RU 486 treatment, a small dose (0.25 mg) of the PGE analogue was given as a single intramuscular injection. The combined treatment resulted in complete abortion in 32 patients (94%). One patient experienced an incomplete abortion and in one patient the pregnancy continued unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Abortifacient Agents, Nonsteroidal↗

Determinants of menstrual bleeding patterns among women using natural and hormonal methods of contraception. II. The influence of individual characteristics.

Menstrual diary records were obtained from women using either a natural method of contraception, a combined or progestogen-only oral contraceptive, a vaginal ring, or a long-acting injectable (DMPA). Within each method group, multiple regression analysis was used to examine the relationships between the subjects' bleeding patterns and their age, age at menarche, ponderal index, obstetric and contraceptive history and ethnic origin. The influence of ethnic origin was described in the preceding paper. Among combined pill users, increasing age was associated with more frequent spotting episodes. In both the untreated and combined pill groups, women with a higher ponderal index had less variable bleeding-free intervals; in the vaginal ring and DMPA groups, the more obese women had shorter bleeding/spotting episodes and longer bleeding-free intervals. Among combined oral contraceptive users, the most influential variable was the time since the end of the woman's last pregnancy: subjects who had been more recently pregnant had longer, less predictable episodes and shorter intervals. Previous oral contraceptive use was associated with more predictable bleeding patterns among women currently using either type of oral pill. In the vaginal ring and DMPA groups, subjects whose last pregnancy had ended in abortion had more bleeding/spotting days and episodes than those who had had a live birth. As reported previously, bleeding patterns were more closely related to the woman's geographical region of residence than to any other factor. The associations found with other individual characteristics were often inconsistent or difficult to interpret. A number of variables which could potentially influence menstrual bleeding patterns, such as nutritional status, were not measured and therefore could not be included in the analysis. However, contraceptive method and ethnic origin may be predominant influences, overriding any other factor.

Abortion, Induced↗

A prospective cohort study of oral contraceptives and cancer of the endometrium.

A prospective cohort study of approximately 97 300 women was conducted in eastern Massachusetts. Information on use of oral contraceptives, and on gynaecological and reproductive histories was sought through mailed questionnaires, while newly diagnosed cases of cancer of the endometrium were identified from records of 34 area hospitals. Oral contraceptive (OC) use was associated with some increase in endometrial cancer rates (standardized rate ratio = 1.4; 95% confidence interval = 0.9-2.4), although the risk did not vary consistently by length of use, years since first use, or age at initial use. Although some subgroups of users had rates of disease higher than among nonusers, there was little to suggest a consistent association between OC use and incidence of endometrial cancer.

Adult↗

Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD.

Thirteen women who were scheduled for hysterectomy volunteered for the study. Nine women had a levonorgestrel-releasing intrauterine contraceptive device inserted between 36 and 49 days prior to surgery and four women were on oral levonorgestrel treatment for 7 days prior to surgery. After the surgical removal of the uterus, samples of endometrial, myometrial, fallopian tube and fat tissue were obtained. Methods for measuring tissue concentrations of levonorgestrel were developed and the uptake of levonorgestrel by fat tissue in vitro was studied. The concentrations of levonorgestrel in myometrial, fallopian tube and fat tissue were all of the same order, of between 1 and 5 ng/g of wet weight of tissue, in both the intrauterine device group and the orally treated group. In the endometrium the levonorgestrel concentrations were many-fold higher in the intrauterine device group. The in vitro experiments showed a rapid uptake of levonorgestrel and an unsaturability of the fat tissue by the steroid at the concentrations used. The fat tissue concentrations of levonorgestrel correlated with the plasma concentrations.

Adipose Tissue↗

Plasma immunoreactive relaxin levels in pregnant and nonpregnant women.

Immunoreactive relaxin was measured in plasma samples obtained from human volunteers utilizing the RIA procedure of Sherwood et al., as modified by O'Byrne and Steinetz for heterologous plasma samples. Immunoreactive hormone was not detected in samples obtained from men, and only rarely in plasma of nonpregnant women. Immunoreactive relaxin was present as early as the fourth week of pregnancy and was detectable throughout the course of gestation. Immunoreactive relaxin tended to be higher early in pregnancy, and there was no peak just before parturition as occurs in many other species. Our results are at variance with those of Bryant and coworkers, who reported high levels of immunoreactive relaxin in men and nonpregnant as well as pregnant women. The possible reasons for this discrepancy are presented.

Contraceptives, Oral, Combined↗

[Can breast cancer be prevented?].

More than six-fold variation in incidence between countries, an increasing incidence among immigrants to high incidence areas, and a general increase in the incidence of breast cancer within countries, are factors which suggest a potential for prevention. Reproductive factors such as early menarche, late age at first full term birth, nulliparity, and late age at menopause increase risk of breast cancer, but manipulation of any one of these factors does not seem to be a realistic preventive tool. Nevertheless, the future possibility of using tamoxifen as a chemopreventive agent against breast cancer is discussed, particularly in relation to women at increased risk due to familial clustering. Alcohol consumption by young women, and overweight among postmenopausal women may also increase the incidence of breast cancer. Consequently, reduced alcohol intake by young women, and weight reduction among overweight women after menopause may reduce the risk of breast cancer.

Adolescent↗

Invasive cervical cancer and depot-medroxyprogesterone acetate. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

Preliminary results of a study of the possible relationship of depot-medroxy-progesterone acetate (DMPA) to invasive cervical cancer are presented. The findings are based on data from three participating centres in Thailand and one in Mexico. A relative risk for cervical cancer of 1.2 was observed in women who had ever used DMPA; this was not statistically significant. No consistent increase in risk with duration of use was observed, although a relative risk of 2 was found in women who had used DMPA for more than 5 years. This observed increase in risk was confined to women who were aged under 46 years or who had first been exposed to DMPA before 30 years of age. These findings are based on small numbers of subjects, and may not represent a causal relationship.

Contraceptive Agents, Female↗