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A randomized double blind study of two oral contraceptives.

To study the question of whether one brand of oral contraceptives may be as acceptable as another for use of publicly-assisted family planning programs, a double blind study of two well-known brands, Ovral and Norinyl, was undertaken in Costa Rica and Trinidad. The pills were randomly assigned to 1,200 women. Common side effects - nausea, dizziness, vomiting, headaches - were associated with both Norinyl and Ovral. Differences in event rates for these conditions were much more marked by country than by the pill used. Ovral was associated with increases in skin problems, notably chloasma, in Cost Rica. A higher percentage of women using Norinyl reported intermenstrual bleeding and spotting in both countries. In Costa Rica continuation rates for Norinyl were adversely affected by this. With these exceptions there appear to be no important differences between the brands that would affect their use in family planning programs.

Adolescent↗

[Changes in heparinocytes during the administration of Depositon and Sequenz-Ovosiston].

During hormonal contraception with Deposiston (once a week pill) and with Sequenz-Ovosiston (14 days mestranol 0.1 mg, 7 days mestranol 0,08 mg and 2 mg chlormadinone acetate) doesn't take place a change of basophil granulocytes (heparinocytes) in blood. Under Deposiston the small elevation is somewhat lengthened, under Sequenz-Ovosiston the elevated phase is similar to those of the normal menstrual cycle. The smaller risk of thromboembolia under heparinocytopenia preventing contraceptives is discussed.

Agranulocytosis↗

Oral contraceptive potencies and side effects.

A set of empirical results is used to test a model that assigns rankings to oral contraceptives in terms of relative hormonal potencies. The association between the observed incidence of side effects attributed to excess of estrogen and progestin and their incidence as predicted by the model is analyzed. Results of the study show the model to have incorrectly predicted the observed ranking order of symptoms associated with excess estrogen. Further, while the model correctly predicted the oral contraceptive with the highest progestogenic potency (Ovral), the observed ranking order of the other two preparations is shown to be the reverse of that predicted by the model.

Clinical Trials as Topic↗

[Cytogenetic studies on women during and following the use of hormonal contraceptives].

The object of our investigations was the assessment of chromosomal changes in lymphocyte cultures of 33 women after long-term application of Ovosiston and Non-Ovlon (Group I), of 10 women with discontinued use of hormonal contraceptives at intervals of at least two month (Group II), cytogenetic investigations of 20 untreated healthy persons (Group III). We did not find an increase of numerical or structural aberrations in all cases. Our study of anomalies in the position of acrocentric chromosomes in the metaphase indicates a significantly increasing rate of associations after long-term use of hormonal contraceptives in lymphocyte culture. Origin connexion and importance of associations were discussed.

Cells, Cultured↗

Effect of ethynodiol diacetate and a combination-type oral contraceptive compound on carbohydrate metabolism. II. One year intravenous glucose tolerance study.

Blood glucose and plasma insulin levels were measured in two groups of women, following one year of oral contraceptive therapy of different types. There were no significant differences from pretreatment glucose and insulin values in the first group of women (on ethynodiol diacetate). In the second group (on norethynodrel and mestranol), there was a significant elevation of mean blood glucose levels in the fasting state and at all times of an i.v. glucose tolerance test. Furthermore, a statistically significant alteration in plasma insulin was observed at all times of the test (except at 120 min). Patients participating in this study will continue this treatment, and results of carbohydrate metabolism monitoring will be reported after 2 years of therapy.

Adult↗

[Effect of oral contraceptives on the psyche and on sexuality].

The problem of whether or not oral contraceptives affect the psychic function of the female is still controversal. The purpose of the present investigation was to study the occurrence of psychic and sexual effects in women taking either Ovosiston (mestranol 0,08 mg + chlormadinone acetate 2, 0 mg) or Non-Ovlon (ethinylestradiol 0,05 mg + norethisterone acetate 1,0 mg). 186 somatically healthy women were subject to two interviews, immediately before the start of therapy and six months after it. Most of the patients recorded distinctly alterations of their mood, their initiative, their elemental desires such as appetite, sleep, need of warmth, and their sexual behaviour. 73 of them noted a change in their emotional pattern, which was positive in 34 and negative in 39 cases. 99 women reported changes in their elemental desires. 136 patients exhibited alterations of their sexual behaviour, which were assessed as an improvement or impairment in 108 and 28 cases, respectively. There is a statistically significant correlation between the impairment of sexual function and the incidence of other untoward side effects. On the other hand, negative suggestion by poor experience of other women on by the influence of mass media seems to play a minor role in producing changes of sexual behaviour. There is, however, a clearcut relationship between negative suggestion and the incidence of unfavourable emotional alterations. The findings are discussed with reference to their clinical significance.

Adult↗

A radioimmunoassay for norethindrone (NET): measurement of serum NET concentrations following ingestion of NET-containing oral contraceptive steroids.

A sensitive and reliable radioimmunoassay (RIA) for the measurement of norethindrone (NET) in serum has been established employing anti-11 alpha-hydroxynorethindrone 11-hemisuccinyl-bovine serum albumin serum in conjunction with norethindrone-3-(0-carboxymethyl) oximino-[125I]-iodohistamine. Of a number of ring A reduced NET metabolites, only 17 beta-hydroxy-17 alpha-ethinyl-5 beta-estran-3-one (43%) and 17 alpha-ethinyl-5 alpha-estrane-3 beta, 17 beta-diol (15.7%) cross-reacted appreciably in this RIA. Ethinyl estradiol (EE2) and mestranol (MEE2) exhibited cross-reactions of only 1.1 and 0.4%, respectively. Serum NET levels were measured in four groups of 3 women, each ingesting either 1 mg NET plus 0.05 mg MEE2 (Norinyl 1 + 50 or Ortho Novum 1/50), 0.5 mg NET plus 0.035 mg EE2 (Brevicon) or only 0.35 mg NET (Micronor) daily for 5 consecutive days. Peak serum NET levels were observed within 1/2 to 4 hours after oral intake and fell precipitously thereafter. After reaching a maximum, serum NET concentrations declined in a manner consistent with at least two disposition phases. The average half-life for the first disposition phase was 2.3, 3.4, 3.9 and 4.4 hours in subjects ingesting Norinyl 1 + 50, Ortho Novum 1/50, Brevicon and Micronor, respectively. Peak and 3-hour post-ingestion serum NET concentrations were dose-related but showed considerable subject-to-subject variations. Following discontinuation of tablet intake, serum NET levels remained detectable (greater than 0.05 ng/ml) for at least 5 days in all 3 women who had taken Ortho Novum 1/50, but in none of the other 9 volunteers. These results suggest that different preparations of identical doses and combinations of oral contraceptive steroids may yield different serum NET profiles. However, due to considerable subject-to-subject variations, larger numbers of subjects are required for a conclusive investigation.

Adult↗

Dynamic testing of hypothalamic-pituitary function in abnormalities of ovulation.

A review of 26 unusual patients indicates that a combined luteinizing hormone-releasing hormone (LRH)-clomiphene test in conjunction with an estrogen provocation test not only was helpful in identifying underlying pathophysiology of anovulation but also proved useful in the clinical management of the patients. Dynamic testing per se does not establish a diagnosis but, in conjunction with history and other laboratory findings, it does make possible further subdivisions of groups of patients who otherwise appear similar, both clinically and from routine laboratory evaluations. It, therefore, tends to pinpoint a lesion and establish the area in which further tests should be made. It is concluded that the value of such investigations will be more evident as gynecologic endocrinology moves into investigation of the supratentorial control of hypothalamic function and as hypothalamic LRH becomes available as a therapeutic agent.

Amenorrhea↗

Comparison of ethinylestradiol and mestranol in sequential-type oral contraceptives in their effects on blood glucose and serum insulin in oral glucose tolerance tests.

Forty 3-hour oral glucose tolerance tests (OGTTs) were performed in 10 assumedly healthy female volunteers 19 to 30 years old, each serving four times as her own control. Each subject was taking a sequential type oral contraceptive containing either 50 microgram of ethinylestradiol or 80 microgram of mestranol alternatingly in four consecutive treatment cycles. The OGTTs were performed on the 6th day of each cycle, during pure estrogen medication. Blood glucose and serum insulin values did not differ significantly under either estrogen as tested by the t-test for paired observations. Our results do not support the findings of others that mestranol has a more pronounced or even exclusively adverse effect on glucose tolerance as compared with ethinylestradiol.

Adult↗

Comparative studies of the ethynyl estrogens used in oral contraceptives. VII. Effects with and without progestational agents on ultracentrifugally fractionated plasma lipoproteins in humans, baboons, and beagles.

Ethynyestradiol and mestranol, in doses ranging from 50 to 100 microgram/day, were given to women in 21-day cycles; baboons and beagle dogs received 1 and 4 microgram/kg/day in a similar regimen. After a number of such cycles, megestrol acetate, norethindrone acetate, or dl-norgestrel was given concomitantly. Protein, cholesterol, triglyceride, and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Over the dosage range studied, the effects of the two kinds of estrogen were indistinguishable. Except for human total plasma triglyceride, no dose-related differences were observed. The lowering of serum protein and the increase in cholesterol induced by estrogen were more pronounced in baboons and beagles than in human subjects. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but absent in beagles. In all three species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by the progestins; in the two animal species, triglyceride is normally very low and the estrogen-induced changes were negligible; the phospholipid rose with estrogen but was unaffected by progestins. In sum, the two animal species show many similarities to, as well as important differences from, the human response of plasma lipids to various contraceptive steroids.

Animals↗

[Effect of oral contraceptive on the pituitary and plasma L.H. levels and on the hypothalamic LH-RH level (author's transl)].

The effects of the oral contraceptive on the pituitary content and plasma level of LH and the hypothalamic LH-RH level were investigated in 16 adult female rabbits. The oral contraceptive preparation, Sophia-C (Norethindrone 2mg + Mestranol 0.1 mg), as administered orally by a stomach tube each day for 7 days in 8 adult female rabbits. At the end of the treatment, the rabbits were bled from the abdominal aorta into heparinized syringes and the plasma was separated. The stalk median eminences were excised. All the materials were stored in -80 degrees C until assayed. Plasma level and the pituitary content of LH and the hypothalamic LH-RH were measured by radioimmunoassay. All the dose response curved were drawn using logitlog transformation. Radioimmunoassay procedures for LH was described in detail elsewhere. Purified rabbit LH for iodination (125-I) and strandard were prepared by T. Makino and R.O. Greep, at Research Laboratories for Human Reproduction, Harvard Medical School, Boston, U.S.A. The starting B/T was 25% at the final dilution of the antibody of 1/20,000. Minimal detectable quantity was about 40 pg/tube. The 50% intercepts were approximately 460 pg/tube. Radioimmunoassay procedures for LH-RH were performed according to the method described by Arimura et al. Antiserum against synthetic LH-RH was kindly supplied to us by Drs. A. Arimura and A.V. Schally, New Orleans, U'S.A. The synthetic LH-RH was kindly supplied to us by Dr. N. Yanaihara. The starting B/T ratio was 29% at the final dilution of the antibody of I/17,500. Minimal detectable quantity was about 40pg/tube and the 50% intercepts were 150pg/tube. It has been assumed that oral contraceptive drugs exert their action by blocking the hypothalamic LH-RH, resulting in a depression of the plasma level of LH, because plasma level of LH returned to the normal level when LH-RH was administered intravenously even while oral contraceptive steroids were given continuously. However, these findings concerning the site of action of the drugs furnished only indirect evidences. The possibility of a direct inhibitary effect of these steroids on the anterior pituitary cannot be ruled out. Administration of 2mg of Norethindrone and 0.1mg of Mestranol significantly depressed both the pituitary content and the plasma level of LH. On the other hand, they significantly increased the hypothalamic LH-RH level. Those findings strongly suggested the direct action of this drug on the anterior pituitary in the female adult rabbits. Detailed mechanisms on how the hypothalamic LH-RH was increased were not known in this experiment, further investigations are now in progress.

Animals↗

Mestranol.

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Animals↗

Investigation of the serum level of pregnancy-associated alpha2-globulin during contraceptive treatment by means of radial immunodiffusion method.

The serum level of pregnancy-associated alpha2-globulin was studied in 70 healthy women taking three different types of oral contraceptives [40 Bisecurin: containing 1.0 mg of Ethynodiol diaceticum +0.05 mg Ethynilestradiol; 20 Infecundin: containing 2.5 mg of Norethynodrel +0.1 mg of Mestranol; 10 Cervicundin: containing of 0.5 mg Ethynodiol diaceticum]. Elevated amounts of serum level of pregnancy associated alpha2-globulin could be detected in 37 of the 40 women taking Bisecurin and in all 20 taking Infecundin. Cervicundin however, failed to induce any change in the serum protein pattern of the 10 subjects studied. Serum levels of pregnancy-associated alpha2-globulin were higher in the Infecundin-taking (53 mg %), than in the Bisecurin-taking group (29 mg %). This shows the oestrogen dependency of the pregnancy-associated alpha2-globulin and points to a possible implication of this globulin in the immunosuppressive processes.

Alpha-Globulins↗

Focal nodular hyperplasia of the liver and contraceptive steroids.

A case of Focal Nodular Hyperplasia of the liver in a young woman taking oral contraceptives is described. The parenteral administration of an elevated dosage of progesterone in a concentrated period of time is a remarkable feature of this case. The vascular alterations, which consisted of a marked increase of arterial and venous formations, intimal proliferation, diffused thrombosis, and the presence of large blood spaces recalling "peliosis hepatis" are the most salient microscopic findings. We should not exclude the possibility that these peculiar vascular alterations be the real effect of steroid hormones on a pre-existent hepatic lesion.

Adult↗