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Effect of oral contraceptive agents on nutrients: I. Minerals.

The epidemiological aspects of oral contraceptive agents on nutrient metabolism were studied in a large population of women. Incidence of clinical abnormalities, related to malnutrition, were more frequently observed in the lower (B) as compared to the higher (A) socioeconomic groups. In the A groups some clinical signs were more common in the nonsupplemented groups of subjects. In general, the intake of oral contraceptive agent subjects for calories, protein, calcium, magnesium, iron, copper and zinc did not differ from the controls. The intake of the above nutrients in group A subjects were higher than those of group B except for calories. The subjects who took supplements had higher intakes of calcium, iron, magnesium and copper. No effect of oral contraceptive agents was seen on hemoglobin, hematocrit and erythrocyte count. Serum iron was increased due to "Norinyl." Total iron binding capacity was increased as a result of oral contraceptive agent administration. Total iron binding capacity values were higher in group B as compared to group A and in the nonsupplemented as compared to the supplemented groups. Plasma copper was increased and plasma zinc was decreased as a result of oral contraceptive agent administration. An increase in erythrocyte zinc was observed due to "Norinyl." No effect of oral contraceptive agents on plasma calcium, magnesium and erythrocyte magnesium was observed. Although no effect of oral contraceptive agents on plasma total protein was found, serum albumin was decreased.

Adolescent

Effect of oral contraceptive agents on nutrients: II. Vitamins.

Clinical, biochemical and nutritional data were collected from a large population of women using oral contraceptive agents. Higher incidence of abnormal clinical signs related to malnutrition were observed in the lower (B) as compared to the higher (A) socioeconomic groups, and also in the nonsupplemented groups as compared to the supplemented groups in the B subjects. As a rule the intake of oral contraceptive agent subjects of vitamin A, C, B6 and folic acid did not differ from that of the controls As expected, subjects from the supplemented groups had higher intake of vitamin A, C, B6, thiamin, riboflavin and folic acid, and A groups had higher intake of vitamin C, B6, riboflavin and folic acid. Increased plasma vitamin A and decreased carotene levels were observed in oral contraceptive agent users. In general oral contraceptive agents had little or no effect on plasma ascorbic acid. Urinary excretion of both thiamin and riboflavin in subjects using oral contraceptive agents were lower in A groups. Erythrocyte folate and plasma pyridoxal phosphate was decreased in A groups due to oral contraceptive agents. Subjects who took supplements had higher levels of plasma vitamin A, ascorbic acid and folate. But urinary thiamin and riboflavin were higher only in group A subjects who took supplements.

Adolescent

Riboflavin deficiency in women taking oral contraceptive agents.

The effect of oral contraceptive agents (OCA) on riboflavin nutritional status of women of child-bearing age in a low socioeconomic population was studied. For a control group, 100 women in the same age and socioeconomic group using alternate forms of contraception were selected. Riboflavin deficiency was determined by measuring erythrocyte glutathione reductase activity, a reliable index of the deficiency. None of the women was on vitamin supplements or had clinical conditions effecting dietary intake or utilization. Eleven of 100 women in the control group had biochemical evidence of deficiency. This compared to 24 of 56 OCA users who were deficient. The frequency of deficiency increased among those on OCA for longer periods of time. Thirteen of 17 OCA users for 3 years or more, compared to 11 of 39 users under 3 years were deficient. There were no discernable dietary differences between the groups. These studies demonstrate that riboflavin deficiency is a problem of women in the lower socioeconomic level in the child-bearing age. The use of OCA aggravates the prevalence of deficiency.

Adolescent

Effect of Ovral, a combination type oral contraceptive agent, on vitamin A metabolism in rats.

When a typical combination-type oral contraceptive agent (Ovral, which contains 0.5 mg norgestrel and 0.05 mg ethinyl estradiol per tablet), is given to young female rats at 50 x the human dosage for an extended period, plasma vitamin A levels are elevated about 50%. The increase is mainly due to a higher steadystate level of retinol binding protein, and not to the presence of more lipoprotein-bound retinyl ester. In Ovral treated rats, the depletion of vitamin A from the liver, calculated as a linear rate, as a linear rate per unit body weight, or as a half-life, tends to be greater, although the differences are only marginally significant. The absorption, storage and short-term excretion patterns of a dose of radioactive vitamin A are not demonstrably affected by Ovral treatment.

Animals

Benign liver cell adenoma associated with use of oral contraceptive agents.

A benign hepatic adenoma in a young woman taking oral contraceptives for 7 years is reported. The diagnosis must be suspected in any young woman taking oral contraceptive agents who develop signs and symptoms of acute cholecystitis with hepatomegaly or mass, or when signs and symptoms of non-traumatic intraabdominal hemorrhage are present. Rupture of the tumor is a life-threatening complication. Treatment should be either hepatic lobectomy or wide local resection.

Adult

Endometrial carcinoma and oral contraceptive agents.

Six patients who took oral contraceptive agents for 5 to 18 years developed endometrial neoplasia. Endometrial adenocarcinoma occurred in 4 of these patients and severe adenomatous hyperplasia occured in 2. Five of the 6 patients took sequential agents; 1 patient used a combined agent. An additional patient who took Premarin and Provera sequentially developed adenocarcinoma of the endometrium. Eighteen cases of endometrial adenocarcinoma and 7 cases of adenomatous hyperplasia in patients with long-term sequential oral contraceptive use have previously been reported by others. Progestogens may not be completely protective against the endometrial cancer-causing potential of the estrogens, especially in the sequential regimens.

Adenocarcinoma

[Results of cytological and histological studies on the uterine cervix after long-term intake of hormonal contraceptive agents].

Cytologic examinations with 880 women having constantly used oral contraceptives from one to eight years show no agglomeration of epithelial atypias if the primary status was clearly in the negative. Among 669 histologically sure atypias of cervix uteri the part of women using oral contraceptives for at least one year is significantly lower in carcinoma in situ as well as in early invasive carcinoma. The differences in dysplasia are not significant. The results are also discussed with regard to the efficiency of permanent control examinations before and during the use of oral contraceptions. The demand of a further intensification of cytodiagnostic is derived from these examinations.

Adolescent

Renal blood flow and its response to angiotensin II. An interaction between oral contraceptive agents, sodium intake, and the renin-angiotensin system in healthy young women.

A variety of estrogen- and progestin-containing oral contraceptive agents reduced renal blood flow (RBF) significantly in 23 healthy, nonhypertensive young women, to a mean of 75 +/- 3.3% of the value expected for their age and dietary sodium intake (P less than 0.001). There was also significant activation of the renin-angiotensin system: renin substrate was increased approximately 3-fold in association with a striking increase in the circulating renin activity and angiotensin II levels in relation to sodium intake and excretion. Two observations suggest that the RBF reduction was directly mediated by angiotensin II. A correlation was demonstrable between circulating angiotensin II and RBF (P less than 0.01), and renal vascular responsiveness to angiotensin II infused into the renal artery was reduced significantly (P less than 0.001). Moreover, the oral contraceptive agents modified the basic relationship between sodium balance and vascular responsiveness to angiotensin II, suggesting that the agents acted through some mechanism other than alteration in the state of sodium balance. These observations provide further evidence for an important role of angiotensin II as a determinant of RBF. Renal vasoconstriction may contribute to the genesis of a number of complications, such as sodium retention and hypertension, associated with oral contraceptive use.

Adult

Plasma renin activity, reactivity, concentration and substrate following hypertension during pregnancy. Effect of oral contraceptive agents.

Plasma renin activity is suppressed in approximately 25% of patients with essential hypertension, and the rate of in vitro angiotensin I production after addition of exogenous renin (renin reactivity) is increased in plasma of hypertensive patients. We have recently observed that blood pressure (116 +/- 1.5/68 +/- 1.7 mm Hg) of young women who had hypertension during a first pregnancy 3--6 years earlier (n = 63) was higher (p less than 0.005) than blood pressure (109 +/- 1.4/61 +/- 1.7 mm Hg) of women who remained normotensive during pregnancy (n = 52). To determine if alterations of the renin-angiotensin axis observed in patients with established hypertension also occur in young adults with relatively high blood pressure, plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate (PRS) and plasma renin reactivity (PRR) were compared in these two groups of subjects. Overall, PRA and PRC were inversely related to systolic blood pressure (p less than 0.02). Excluding women on oral contraceptive agents, the PRA response to standardized treadmill exercise was suppressed (less than 1.0 ng/ml/hr) in 19% of women with a history of hypertension during pregnancy and in no women who remained normotensive throughout a previous pregnancy; PRR did not differ (p greater than 0.8) in the two groups of young mothers (27.1 ng/ml/30 min +/- 1.2 SE VS 26.2 ng/ml/30 min +/- 0.9 SE). Thus, renin suppression, but not increased PRR, precedes the onset of hypertension. Oral contraceptive usage was associated with higher systolic blood pressures, increased PRS, and low PRC. Highest blood pressures and lowest PRA occurred in women with a history of hypertension during pregnancy who were taking oral contraceptive agents at the time of study.

Adolescent

Steroid contraceptive agents and immunological reactivity in experimental animals.

The immunodepressive activity of widely employed steroid contraceptive agents (SCA's) was evaluated in mice and rats on various humoral and cell-mediated responses. Three different progestagens (lynestrenol, norethindrone or norethynodrel) were administered in combination with the estrogen mestrahese SCA's could significantly reduce the severity of allergic encephalomyelitis in rats, variations in their capacity to interfere with primary response to sheep erythrocytes in mice and anti-mouse erythrocyte autoantibody formation were found. Treatments employed with these SCA's did not reduce tumor allograft resistance in mice and the anti-sheep erythrocyte response in rats. In addition, otherwise immunosuppressive treatments with these SCA's did not modify the mouse response to a T-independent antigen. The possible clinical significance of these results is discussed.

Animals

Cycle control with triphasic norgestimate and ethinyl estradiol, a new oral contraceptive agent.

Effective cycle control was demonstrated based on two multicenter, 2-year studies of the triphasic oral contraceptive (OC) agent containing the new progestin norgestimate. The estrogen in this OC is ethinyl estradiol. These open-label Phase III studies were conducted in the United States by 33 investigators at 33 sites who treated a total of 1,783 subjects, healthy women 17 to 38 years of age with menstrual cycle characteristics considered to be within the normal range. The norgestimate/ethinyl estradiol preparation was taken for up to 24 cycles. Follow-up information was collected 3 to 4 months post-treatment. Bleeding pattern analyses were based on 27,970 valid cycles. Normal cyclic bleeding patterns were experienced by most of the women during the study; only minimal and statistically and clinically insignificant variations in menstrual flow, dysmenorrhea, and premenstrual tension occurred. There was a low incidence of failed withdrawal bleeding in single cycles (less than 1.0% after cycle 6). There were no cases of amenorrhea, defined as two consecutive cycles of missed withdrawal flow. The incidence of breakthrough bleeding or spotting was highest during the initial treatment cycles and diminished with continued use of the formulation. The mean incidence of breakthrough bleeding was 2.36% in cycles 13 to 24. Apart from somewhat higher initial percentages among women new to oral contraception, the pattern of midcycle bleeding or spotting was similar to that of all women studied. Effective long-term cycle control was demonstrated in women who used this OC agent.

Adolescent

Effect of oral contraceptive agents on thiamin status.

A cross-sectional and follow up study of oral contraceptive agent (OCA) users revealed no adverse effects of OCA on erythrocyte transketolase activity (ETK) or thiamin pyrophosphate effect (TPP effect). In the cross-sectional study group, thiamin intake was below the recommended in only 19.2 per cent subjects and thiamin intake/100 kcal/day revealed a significant negative correlation with TPP effect. Routine prophylactic administration of thiamin was not indicated in OCA users.

Adolescent