Effects of the antifertility drug enovid in five strains of mice, with particular regard to carcinogenesis.

PIP: The antifertility drug, Enovid, was tested for possible carcinogenicity in female mice of 5 specially selected strains: BALB/c, C3H, C3HfB, A, and C57BI. Enovid was chosen for testing since it is one of the most widely used oral contraceptives. The 5 strains of mice provided maximum genetic variation in the test animals. The drug was fed at 3 dose levels: 5 mcg/gm, 10 mcg/gm and 20 mcg/gm of food. The lowest dose did not prevent reproduction. The 10 mcg dose prevented some females from reproducing. The 20 mcg dose prevented all females from reproducing. The strains of mice differed in their response to Enovid. Weight gain was reduced in all strains. Effect on life-span varied, partly because of the tumors. Cervical and vaginal lesions showed invasion of the epithelium into the stroma but was limited, with few exceptions to the BALB/c females. In the BALB/c strain these lesions occurred in controls as well, but showed more progression and a higher incidence with the highest dose of Enovid. None of these lesions appeared grossly as tumors and none had extended beyond the vaginal wall or metastasized. They were observed only on histologic sections. Neither ovarian nor mammary gland tumors were increased in any strain. In the C3H strain such tumors seemed to be inhibited. In the C3HfB strain there was some inhibition of hepatomas and in the BALB/c strain some inhibition of adrenocortical adenoma. Chromophobe adenomas of the hypophysis were significantly increased in old C57BI females treated with the highest dose of Enovid. Offspring of Enovid-treated females showed no abnormalities. Enovid increased the occurrence and may have advanced the progression of epithelial lesions of the cervix and vagina of old BALB/c females. A study of the lesions in untreated females of this strain might help the understanding of carcinoma in situ in women and possibly the appearance of adeno-carcinoma of the vagina of young women whose mothers had been treated with stilbestrol during the first trimester to maintain pregnancy. Other neoplasms in this strain were not increased by the Enovid therapy. In the C3H strain mammary tumors were reduced by the Enovid and those that did occur were found later than in controls. Results from experimental animals should be applied to humans with care. Such results are of greatest value in directing attention to certain areas for investigation.^ieng

Tryptophan metabolism in women using steroid hormones for ovulation control.

PIP: This is an extension of work recently reported by Rose regarding young women using a combination of progesterone and estrogen for ovulation control. The 10 subjects studied had an abnormal xanthurenic acid excretion after a loading dose of tryptophan. After treatment with 2.5 mg norethynodrel and .1 mg mestranol (Enovid-E) from Days 5 to 24 of the the cycle, 24-hour urine specimens were collected before and after administration of 2 gm of L-tryptophan. They were then given 25 mg of pyridoxine hydrochloride 4 times a day during the 48 hours required to repeat the tryptophan loading test. Controls were 18 healthy women not taking drugs. Metabolites of trytophan determined were indican, anthranilic acid glucuronide, 0-aminohippuric acid, kynurenic acid, acetylkynurenine, kynurenine, 3-hydroxykynurenine, xanthurenic acid, and N-methyl-2-pyridone-5-carboxamide. Urine specimines were analyzed for these and for 4-pyridoxic acid taking usual precautions to avoid dietary factors or drugs which might vitiate the results. At first the ingestion of the steroid had no significant effect on the basal excretion of urinary tryptophan metabolites. However, after the loading dose of tryptophan, the subjects taking Enovid E- excreted a mean level of 697 micro-moles of xanthurenic acid compared with a mean level of 29.8 micro-moles in controls. Some of the other metabolites were also excreted in increased quantities: 3-hydroxykynurenine, kynurenine, kynurenic acid, and acetylkynurenine. The others were excreted in normal quantities. When experimental subjects were given 100 mg/day of supplemental pyridoxine hydrochloride, tryptophan metabolism was essentially normal. These results should be considered in human metabolic studies of pyridoxine-requiring enzyme systems.^ieng

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.

PIP: 18-45 year old women were tested to determine if the use of oral contraceptive agents (OCAs) affects the metabolism of vitamins. 4 different hormonal conditions and 2 socioeconomic levels in 8 groups were considered. Some of each socioeconomic level had taken Norinyl (1 mg norethisterone and 50 mcg mestranol) for 3 months or more. Others had used Ovral (.5 mg norgestrel and 5 mcg ethinyl estradiol) for equal periods. There were some in each group who had resumed use of OCAs during lactation within 5 weeks after pregnancy. Vitamins and mineral supplements were given to groups in each socioeconomic classification. They had a higher intake of Vitamins-A, C, thiamin, riboflavin, and folic acid. Incidence of clinical sings of malnutrition, such as dry skin, easily pluckable hair, angular lesions of the mouth, dental caries, bleeding gums, glossitis, and scaling of the skin, were significantly more frequently observed in the lower socioeconomic groups, and especially in nonsupplemented groups of women taking OCAs than in others. OCA administration increased plasma Vitamin-A levels but no socioeconomic effect was found. Plasma carotene levels were decreased by OCA therapy, but less so in the higher socioeconomic subjects. Plasma ascorbate was not affected by OCA use. Urinary excretion of thiamin annd riboflavin was decreased in subjects using OCAs. Erythrocyte folate and plasma pyridoxal phosphate (PLP) were also decreased. Results show a definite lowering effect of OCAs on red cell folate in subjects in the upper socioeconomic levels. There may also be a depletion of body stores of folic acid. It has been suggested that women who become pregnant soon after discontinuing OCA therapy have a high chance of developing folic acid deficiency during pregnancy. The lower socioeconomic group may be marginally deficient in folic acid. Similar results were obtained with thiamin and riboflavin. Changes due to OCA use with respect to thiamin, riboflavin, folate, and PLP were seen mainly in subjects in the upper lower socioeconomic groups may have prevented detection of smaller similar alterations due to OCA use.

Proceedings: Quantitation of a new serum alpha-macroglobulin in malignant disease, steroid treatment, pregnancy and normal subjects.

PIP: Alpha-macroglobulin was quantitated in patients with malignant disease, steroid treatment, pregnancy, and in normal subjects using the rocket technique of Laurell. Women treated with combined estrogen/progestogen and with mestranol and men treated with stilbesterol showed rises in alpha-macroglobulins. Those treated with norethynodrel did not, indicating that the estrogen is the responsible agent. The level increased during pregnancy and decreased sharply in the first 2 days postpartum. 30% of normal women and 10% of normal men had detectable quantities of the protein (up to 4 mg/100 ml) in their serum. 92% of patients with malignant disease had detectable levels of protein--6 mg/100 ml or higher.^ieng

Effect of long-term therapy with an oral contraceptive on some aspects of hepatic lipid metabolism in vitro.

PIP: The effect of Enovid (7.5 mg/kg of food) for both short and long periods of therapy in female Blue Spruce Farm rats was studied. Hepatic release of triglyceride and of cholesterol was measured. Tests were made in vitro. Treatment periods were 4 days of 1 year. The short-term treated group ingested 315 mcg/kg body weight of Enovid daily; the long-term treated group ingested 375 mcg/kg of body weight of Enovid daily. These are about 3 times the daily dose for humans. Animal livers were removed and placed in a perfusion apparatus. The perfusion technique is described. The adrenal glands were also removed and the lipid extract, after being similarly treated in the perfusion apparatus, was tested for cholesterol. Body weights of animals were reduced significantly (p less than .05) by both short- and long-term treatment. The amounts of food consumed were reduced only in the short-term tests. In neither group was change in liver weight found. Bile production was reduced 50% in rats treated 4 days but in those treated 1 year with Enovid no effect was noted when compared with controls. However, in both control and test animals, production of bile after 1 year was reduced by 70-75% as compared with younger animals. Perfusion flow rate in rats treated with Enovid for 1 year was significantly faster (p less than .02) than through livers in the control group. Glucose release was reduced by both short- and long-term Enovid therapy. Reduced food intake may have caused this effect in the short-term therapy. In the group treated with Enovid for 1 year, release of cholesterol and triglycerides into the perfusate was reduced 72 and 38%, respectively. This effect was not observed in the 4-day treated animals. Enovid had no effect on the weights of livers or on the concentration of either triglycerides or cholesterol in hepatic tissue after either form of therapy. No elevation of serum triglyceride was found. A 30% decrease in serum cholesterol was found after 4 days of Enovid therapy. However, in those treated 1 year, and in controls, there was a 100% increase over that of younger animals. Enovid had no effect on the weights of adrenal glands. Total sterol content of adrenal glands from animals treated 1 year was decreased significantly (p less than .05) but not in animals treated only 4 days. Results obtained may be attributed to the metabolic effects of the individual components of Enovid. Further experiments are in progress to examine the effects of each component on hepatic triglyceride transport. Each Enovid tablet contained 5 mg norethynodrel and .075 mg of mestranol.^ieng

Hypertriglyceridemia during treatment with estrogen and oral contraceptives. An alteration in hepatic function?

PIP: Impaired glucose tolerance in 49 women taking Envoid (5 mg norethynodrel, .075 mg mestranol) is reported and evidence that mestranol is the disposing factor is presented. 23 of 38 (61%) women who had taken the drug for more than 10 months had triglyceride levels greater than 110 mg/100 ml. Generally, triglyceride levels increased with the duration of treatment. However, cholesterol levels were not markedly increased. Administration of mestranol alone resulted in a prompt increase in plasma triglyceride levels. Except for 1 woman who had been under long-term Enovid treatment, triglyceride levels returned to normal soon after discontinuation of treatment. The results suggest that hypertriglyceridemia resulting from oral contraceptives containing estrogens is due to an alteration in liver function.^ieng

Reversible "cancer" and the contraceptive pill. Report of a case.

PIP: This is a case report of a hyperplastic lesion of the endocervix which histologically and clinically mimicked cancer in a patient using a contraceptive pill. The 24-year-old woman had been taking Enovid-E for 1 year. She was diagnosed as having advanced cervical cancer; a large granular erosion of the cervix and several vaginal cysts were in the region of a former episiotomy. Cone biopsy of the cervix and excision o f the lesions were interpreted as carcinoma in both. However a vaginal smear was reported negative. On reexamination the lesions were atypical, softer and with less surrounding induration than expected for cancer. Review of the histologic sections showed that, although a malignant architectural pattern was present, the individual cells lacked the essential malignant characterisitics. Oral contraceptives had not been taken for 1 month and no more were given. Follow-up examinations a t 2-week intervals showed gradual recession of the lesions. Vaginal smears continued negative. A hysterectomy was done; removed tissues showed no evidence of malignancy. There was residual cystic hyperplasia of atypical glands. The patient's subsequent course has been uneventful. The lesions are regarded as having been florid hyperplasia of endocervical glands and of similar epithelium in the lower vagina. S everal experienced gynecologists and pathologists had originally accepte d the lesions as malignant. This is a rare complications of a hormonal contraceptive.^ieng

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.

PIP: Oral contraceptive (OC) potencies and the side effects attributed to excess estrogen and progestin were analyzed by the use of a model that assigns rankings to OCs in terms of relative hormonal potencies. 480 healthy women were randomly assigned Ovral, Norinyl, or Norlestrin. The results show that Ovral users have significantly (.01 or = p or = .05) higher incidence of symptoms but Norinyl users more frequently reported symptoms of progestin excess than Norlestrin users. The results show the model to have incorrectly predicted the observed ranking order of symptoms associated with excess estrogen while the model correctly predicted the OC with the highest progestogenic potency (Ovral). The observed ranking order of Norinyl and Norlestrin was the reverse of that predicted by the model.

Thyroid status in long-term, high-dose oral contraceptive users.

PIP: The effect of high-dose, long-term oral contraceptive use on thyroid function and thyroid disease was investigated. Between 1956 and 1962 there were 836 patients treated with Enovid. Initially doses of 10 mg were given, then 5 mg, and finally 2.5 mg. 53 patients used oral contraceptives continuously through a total of 8111 cycles with an average of 156 cycles and an average dose of 3.75 mg/day/cycle. These 53 women were studied for protein bound iodine (PBI), resin triiodothyronine (T3) uptake, total thyroxine (TT), free thyroxine level (FT), radioiodine uptake, and a thyroid scan. Fractional uptakes were done on some. The PBI, T3, TT, and FT tests were done at the Bio-Science Laboratories in California, the others at a local laboratory. Uptake values were abnormally low in 40% of patients. This finding had not been previously reported. Thyroid scannings for 48 patients showed 44 were normal. In 3 patients the thyroid appeared uniformly enlarged but this was not apparent on physical examination. A small cold area was noted in 1 thyroid. No nodule or other variation was found on physical examination. A combination of the PBI test and T3 would be most helpful in evaluating hypo or hyperthyroidism. In the presence of a nontoxic goiter the PBI would be normal or high and the T3 normal or low. Though individual tests showed alterations no definite e vidence of thyroid disease was found in the patients studied.^ieng

Influence of norethynodrel and mestranol upon cervical dysplasia and carcinoma in situ.

PIP: A 3-year progress investigation of the results of continuing serial cytologic, cytochemical, colposcopic, histologic, and clinical studies i nvolving 782 women is reported. These patients were selected from 60,00 0 women by a cytodiagnostic screening group before medication was given. The drug used was the steroid contraceptive Enovid, a combination of 9.85 mg norethynodrel with .15 mg mestranol. The usual daily dose of Enovid was 2, 5, or 10 mg orally. Tablets were taken in 20 doses from D ay 5 to Day 24 of the menstrual cycles. In some, continuous therapy was given at the same dosage for 60-240 days. Response was not related to dosage. Medication was begun after a cell-diagnosis was made. Frequent periodic examinations were made of cells scraped from the squamo-columnal junction of the cervix. This method was considered much more accurate than smears from the vaginal area. Some were followed for 3-4 years. No case was found in which a lesion progressed to a stage of infiltration. In the 654 women found to have normal cytology, Enovid therapy appeared to have exerted no unfavorable influence. Of the 66 women who had preexisting inflammatory lesions with precancerous tendencies, slight progression was noted in 2 (6%) and remission in 20 (30%). In 42 (64%) no change was found after Enovid medication. Of 60 patients having marked dysplasia of cells or with beginning carcinoma in situ, 3 (5%) showed remission, 15 (25%) showed fluctuation of findings, and 42 (70%) showed unaltered expected progression. Cytochemical investigations included continuing fluorescent microscopic studies to evaluate changing levels of DNA and RNA, glycogen studies, and micropolysaccharide evaluations. It is concluded that Enovid showed no carcinogenic influence even in preexisting premalignant dysplasia or carcinoma in situ of the cervix. However, periodic examinations with cervical cytologic studies are recommended for those under Enovid medication.^ieng

Methodology in oral contraceptive research.

PIP: There has been speculation as to what constitutes sufficient investigative clinical data to establish the efficacy of oral contraceptives. The obstetric and gynecology advisory board of the U.S. Food and Drug Administration has recommended that 4000-5000 woman-cycles of treatment yield a meaningful pregnancy rate before the oral contraceptive is termed effective. A clinical experience with oral contraceptives is presented. 4977 patients were treated through 51,544 woman-cycles with only 1 questionably unplanned pregnancy. If this pregnancy is considered as a method failure, it represents a pregnancy rate of .02. In such a study, when no pregnancies occur, the upper confidence level for pregnancy probability may be statistically calculated. From the data available it appears that the U.S. Food and Drug Administration's obstetric and gynecology advisory committee recommendation of 4000-5000 cycles will provide the physician with a statistically significant evaluation of efficacy.^ieng

Menstruation in women with normal or artificially controlled cycles.

PIP: Menstrual flow was measured daily during menstruation by means of intravaginal cups in 30 women not taking steroids and in 12 women who were taking steroids orally for contraceptive purposes. In the group of women not taking steroids, a wide variation in individual flow rates was observed, the greatest menstrual loss occurring during the first 48 hours of the peroid. 1 woman using an IUD exhibited an average hourly discharge exceeding the range in controls. Menstrual flow in women taking synthetic progestin and estrogen in combination for contraceptive purposes was only 1/3 that observed in nonsteroid controls during the first 2 days of menstruation. A daily variation in menstrual discharge volume did not occur. It is postulated that in women taking oral contraceptives, alterations in menstrual physiology may be related to morphologic changes in the uterus.^ieng

The relative expressed estrogenicity of oral contraceptives.

PIP: Total effective estrogenicity of several human oral contraceptives was investigated through a method determining uterine weight in immature rats. The preparations, normally given to human females in tablet, form were Norinyl-1 (.05 mg mestranol, 1mg norethindrone), Norinyl-2 (.10 mg mestranol, 2 mg norethindrone), Ovulen (.10 mg mestranol, 1mg ethynodiol diacetate), Enovid-E (.10 mg mestranol, 2.5 mg norethynodrel), and Enovid-5 (.075 mg mestranol, 5mg norethynodrel). Each products was administered in total doses of .0025, .005, and .01 of a tablet. Each dose had 3 trials, approximately 10 mice to a trial. Each mouse was given the compound in .2 ml aqueous vehicle orally, daily for a 3-day period so that the sum of the daily doses equaled 1 of the tablet fractions above. Autopsy, on Day 4, discovered the ratio of mg uterus/gm body weight. A .0025 fraction of a tablet of Norinyl-1 produced a mean uterine ratio of 1.79, while control (untreated) mice had a mean ratio of 1.06. Norinyl-2, Ovulen, Enovid-5 and Enovid-E, judging from the corresponding increases in ratios from the control ratio, were found to be 2.1, 2.7, 6, and 8 times, respectively, more estrogenic than Norinyl-1. The relatively high estrogenicity of the Enovids is probably due to the conversion of norethynodrel to estrogenic compounds.^ieng

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.

PIP: A sensitive and reliable radioimmunoassay (RIA) for measuring norethindrone (NET) in serum is described. Of a number of ring-A-reduced NET metabolites, only 2 cross-reacted appreciably in this RIA. Ethinyl estradiol and mestranol exhibited cross-reactions of only 1.1 and .4%, respectively. Serum concentrations of NET before and after ingestion of 4 NET-containing oral contraceptives (OCs) by 3 women each were measured by this RIA. In all 12 volunteers, serum NET levels rose rapidly after oral intake, reaching peak levels within .5-4 hours (median, 1.5) and fell precipitiously thereafter. Peak serum NET averaged 10.2 ng/ml after Ortho Novum 1/50 ingestion, 10.4 after Norinyl 1+50, 7.5 after Brevicon, and 4.3 after Micronor ingestion. Individual peak NET levels varied considerably in each group. Average half-lives varied from 2.3-4.4 hours, depending on OC compound ingested. After discontinuation of OCs, serum NET levels remained detectable ( .05 ng/ml) for at least 5 days in all 3 women who took Ortho Novum 1/50 but in none of the other subjects, suggesting that different preparations of identical doses and combinations of OCs may yield different serum NET profiles.

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.

PIP: A double-blind study of 2 well-known brands of contraceptives, Ovral and Norinyl, was performed in Trinidad and Costa Rica to determine if 1 brand of oral contraceptive were as acceptable as another. Differences in race and ethnic origin were large between the 2 study populations. There were no significant differences in reporting of gastrointestinal side effects for the 2 formulations. Women using Ovral in Costa Rica reported acne and chloasma in significantly greater (P .001) numbers than did women using Norinyl. Participants in Trinidad were virtually free of such complaints. Overall in both study populations, Ovral affected significantly more users (P .05) both with regard to chloasma and all skin conditions than did Norinyl. A moderate excess of cervicitis and cervical erosion among Ovral users in Trinidad was seen; in Costa Rica, cervical erosion occurred in 13% of users of either drug, whereas cervicitis was noted in 3% of each group. Both brands reduced the average number of days of menstrual bleeding in the 2 countries, and both formulations effected a reduction in the % of women reporting relatively heavy menstrual flow. Intermenstrual spotting or bleeding was strongly (P .001 overall) associated with the use of Norinyl; in both countries, the % of women using Norinyl reporting intermenstrual bleeding was at least 2 times that of Ovral users. In Costa Rica, continuation rates for Norinyl were badly affected by the frequency of intermenstrual bleeding (27.9 for Norinyl and 8.2 for Ovral). Otherwise, it is concluded that there were no important differences between the 2 formulations.

Influence of oral contraceptives on circulation immune response. I. Effect of combination type contraceptives.

PIP: Female mice were given either Ovral or Enovid orally and studied to determine what effect the combination oral contraceptive agents (OCAs) had on circulating levels of tetanus antitoxin. Ovral produced significantly lower titers of circulating tetanus antitorin (p.005); the titers decreased with increasing doses of Ovral. Enovid produced borderline significant lowering (.1p.05). Clearance of tetanus antitoxin in mice given Ovulen or Ovral was not greater than in control mice, and treatment with Ovulen or Ovral did not change tetanus antitoxin titers in actively immunized mice. It is concluded that combination OCAs may interfere with antibody synthesis.^ieng

Invluence of oral contraceptives on circulating immune response. II. Effect of progestogenic and estrogenic components.

PIP: Female mice were treated with chlormadinone acetate (.25 mcg or 6.25 mcg), megestraol acetate (.25 mcg or 6.25 mcg), ethynodiol diacetate (.5 mcg or 12.5 mcg), norgestrel (.25 mcg or 6.25 mcg) or norethynodrel (2.5 mcg or 62.5 mcg) and studied to determine what effect these progestagens had on circulating tetanus antibody titers. None of the progesterones affected the immune response to tetanus toxoid. Mice given ethinyl estradiol or mestranol had enhanced circulating antibody titers. It is conlcuded that combination oral contraceptives act to diminish antibody response as a result of the combined potency of the estrogen and progesterone components.^ieng

Oral contraceptive-alpha-tocopherol interrelationships.

PIP: After observing that some of the side effects of the administration of oral contraceptive drugs to rats resemble those resulting from vitamin E deficiency, a possibility of an increased requirement for vitamin E during oral contraceptive therapy was considered. 4 groups each of 22 female weanling rats were placed on a 15% stripped corn oil diet adequate in all required nutrients except alpha-tocopherol. Group T had .01%, d,1-alpha-tocopheryl acetate incorporated into the diet; Group B had .05% butylated hydroxytoluene (BHT); Group N and NT had no additives. After 10 weeks when daily dosing with Enovid E (.052 mg in .1 ml propylene glycol) was initiated, Group NT was changed over to the tocopherol containing diet. The dosing continued for 4 days for half of the animals and for 28 days for the other half (Groups E) at which time the animals were sacrificed. 8 animals in each group served as a control and received the propylene glycol carrier only (Groups C). During the short experimental period, most of the animals lost weight whereas the long period of dosing resulted in lower gains in the vitamin E deficient than in E sufficient rats. Results showed that the effects of an oral contraceptive were less pronounced in E deficient rats. Lowering of plasma tocopherol levels was observed in rats receiving the drug. The vitamin E deficiency and the stress induced by the administration of an oral contraceptive were definitely not synergistic. It follows then that oral contraceptives do not aggravate biochemical changes when tocopherol status is inadequate.^ieng

Long-term experience with Enovid among clinic patients: results after 2 and one-half to 6 years of individual patient use.

PIP: 64 women clients of Planned Parenthood of Evansville (Indiana) used Enovid (5 mg norethynodrel and .075 mg mestranol, combined) for 2 1/2 to 6 years. A "25-Month Club" card and free pills were given to encourage continuation in the study, and 33 women (52%) remained until study termination. The group ranged in age from 18-40 years, mean 27 years, and in parity 0 to 12, mean 4. No pregnancies, cancer of reproductive organs or thromboembolism occurred. Side effects, recorded by interview according to a standard form, included: cervicitis 48%, vaginal discharge 42%; dysmenorrhea 61% pretreatment, 42% improved, 11% new symptoms; breast complaints 33%; 2-15 lb weight gain 19%. 12% reported no side effects, although the author commented that the 25-Month Club policy might have discouraged reporting of side effects.^ieng

Changes in sexual drives of patients on oral contraceptives.

PIP: 169 married and 42 single women attending the Family Planning Clinic at Wilford Hall U.S. Air Force Medical center were surveyed over a 4-month interval to study changes in sexual drives associated with oral contraceptives (OCs). 74.4% reported they were without side effects. The menstrual flow was decreased in 62% and increased in 4%. Duration of the menstrual cycle was decreased in 57% and unchanged in 41%. 34% indicated less dysmenorrhea while taking OCs. There were some differences between married and single women when questioned about their sexual drive. 68% of the married women and 71% of the single were without change in their libido. 21% of the married women felt that their libido diminished. 22% of single women experienced increased libido. 31% of the single women had a heightened sexual response while only 17% of the married women reported this. Sexual activity increased in 40% of the single women and 16% of the married women. Libido decreased as family size increased. There were only minor differences in changes among those who use different OCs. There was a progressive decrease in libido, sexual response, and sexual activity during the first 2-3 years of medication. After 5 years, however, sexual response was progressively heightened. Fear of pregnancy was uniformly lessened with OCs in 72-75% of all patients. Individuals may have changes in their sexual drives secondary to OCs. However, as many have increased as have decreased drive.^ieng