Altered haemorheology in oral-contraceptive users.

The haemorheological profile of the menstrual cycle was determined in 12 women who did not take oral contraceptives and compared with that in two groups of women (n = 8 and n = 30) who had been taking oral contraceptives for at last six months. Packed cell volume, platelet count, erythrocyte deformability, plasma fibrinogen concentration, and plasma and whole-blood viscosity varied cyclically throughout the menstrual cycle in the 12 non-users. This variation was abolished by the use of oral contraceptives, and the values of these indices were raised by an amount likely to predispose to thrombosis.     

Isometric strength and endurance during the menstrual cycle.

Seven healthy young women, 3 whom had been taking oral contraceptives, were examined during the course of 2 menstrual cycles to assess their isometric strength, their endurance during a series of 5 fatiguing isometric contractions at a tension of 40% MVC, and their blood pressures and heart rates during those fatiguing contractions. Two sets of experiments were performed, one in which the subject's forearm temperature was allowed to vary as a function of T A, and one with the muscle temperature stabilized by immersion of the forearm in water at 37 degrees C. During exposure to ambient temperatures, isometric strength and both the heart rate and blood pressure responses at rest and at the end of a fatiguing, sustained isometric exercise, were not significantly different during any phase of the menstrual cycle in any subject. In contrast, the isometric endurance in the women not taking oral contraceptives varied sinusoidally in all 5 contractions with a peak endurance midway through the ovulatory phase and the lowest endurance mid-way through the luteal phase of the menstrual cycle. The isometric endurance of the women taking oral contraceptives did not vary during their menstrual cycle. After stabilization of the temperature of the muscles of the forearm in water at 37 degrees C, the isometric endurance of the normal subjects showed a hyperbolic response with the maximal endurance at the beginning and end of their cycles, and the shortest endurance at mid-cycle. Here again, however, the isometric endurance of the women taking oral contraceptives did not vary after immersion of their forearms in the 37 degree C water.     

Depressive Symptoms and Oral Contraceptives

Of 261 women who completed a self-rating scale for measuring depression, 168 were taking oral contraceptives and 93 were using physical methods of contraception. Of the group of women taking oral contraceptives 6·6% were more severely depressed than any of the control group. There was a significant variation in the depth of depression related to the day of the menstrual cycle in the control group. This association was not found in the oral contraceptive group, where premenstrual depression was limited to the one or two days preceding menstruation.Women taking a contraceptive containing lynoestrenol 2·5 mg. and mestranol 0·075 mg. showed a significantly increased incidence of pessimism, feelings of dissatisfaction, crying, and tension, compared with women taking other oral contraceptives and the control group.     

Influence of contraceptive pill and menstrual cycle on serum lipids and high-density lipoprotein cholesterol concentrations.

The fluctuations of serum lipid and lipoprotein concentrations within one cycle were studied both in women using and not using oral contraceptives. High-density lipoprotein cholesterol decreased significantly from 1.47 mmol/l (57 mg/100 ml) to 1.30 mmol/l (50 mg/100 ml) during one contraceptive cycle in eight women and rose again to the initial value during the pill-free days. The mean concentration of total cholesterol also fell significantly as a result of the decrease of high-density lipoprotein cholesterol and of a not significant decrease of low-density lipoprotein cholesterol. The mean serum triglyceride concentration did not change significantly. The fluctuations in the concentration of serum lipids and lipoproteins in 10 women not using oral contraceptives were smaller than in the women using oral contraceptives and no significant changes in the concentrations were found during one cycle. Thus, high-density lipoprotein cholesterol concentration decreases during each contraceptive cycle. The time of blood sampling during the cycle is, therefore, of vital importance in interpreting the effect of oral contraceptives on high-density lipoprotein cholesterol. In women not using oral contraceptives blood can be sampled on random days during the cycle.     

Proceedings: Correlation of various clinical parameters with glucose tolerance test in women using oral contraceptives

A study was carried out to determine whether oral contraceptives affect carbohydrate metabolism as assessed by glucose tolerance curves. Glucose tolerance tests were carried out in seventy-six women. The women were divided into two groups. The first group constituted the control and the second group comprised women taking combination oral contraceptives. The glucose tolerance curves were correlated with: (1) the duration of thereapy; (2) the family history of diabetes; (3) the obstetric history; (4) age: (5) weight gain; (6) parity; and (7) changes in blood pressure. The combination type of oral contraceptives were observed to affect adversely the glucose tolerance test. A significant correlation was recorded between the familial diabetic history, intake of combination contraceptives and abnormal glucose tolerance tests. A history of birth of a large baby was found to be an important indicator of abnormal values of glucose tolerance in women taking a combination type of oral contraceptive. Such women showed an abnormal curve pattern at a much earlier age in life compared with controls. It was also observed that a high percentage of women who had gained excessive weight on combination contraceptives had an altered glucose tolerance test. Parity and blood pressure were two parameters which did not reveal any correlation with abnormal glucose tolerance curves.     

Vitamin A,Pregnancy, and Oral Contraceptives

It has been shown that women receiving oral contraceptives have increased levels of serum vitamin A. High vitamin A levels may constitute a teratogenic hazard and it has been suggested that women who conceive soon after discontinuing oral contraceptive therapy may be especially at risk to this hazard.We have confirmed a significant increase in vitamin A levels in women taking oral contraceptives. During early pregnancy there is no significant difference in vitamin A levels between women who have recently been taking oral contraceptives and those who have not. We have been unable to show that either taking oral contraceptives shortly before pregnancy or a high vitamin A level during the first trimester of pregnancy, comparable to that of a woman taking oral contraceptives, has any detrimental effect on the outcome of pregnancy. It seems unlikely that women who conceive soon after discontinuing oral contraception run any teratogenic risk from increased vitamin A levels.     

Amenorrhoea after Discontinuing Combined Oestrogen-Progestogen Oral Contraceptives

Out of 210 women seen at the Middlesex Hospital with secondary amenorrhoea the 63 who developed it after stopping oral contraceptives were fully investigated. Five had organic disease sufficient to account for the amenorrhoea (one had severe diabetes, one a pituitary tumour, and three premature ovarian failure); two patients had galactorrhoea (one of whom also had the pituitary tumour); two had anorexia nervosa.Of the 63 women 40 (63%) had suffered from amenorrhoea or prolonged or irregular menstrual cycles before taking the pill, and this suggested that combined oestrogen-progestogen oral contraceptives should be used with caution for women with irregular menstruation.Nineteen patients wished to become pregnant and 12 have so far done so after treatment with clomiphene or gonadotrophins.In another study 204 women recorded when their first menstrual cycle occurred after stopping the pill. Seventy-four had a cycle longer than five weeks but only five exceeded three months, and only one of the five had more than six months'' amenorrhoea. These results confirm that the incidence of amenorrhoea after stopping oral contraceptives is low.     

Effects of menstrual cycle phase and oral contraceptive use on verbal memory

Surgical or pharmacological suppression of ovarian hormones leads to declines in verbal memory, and estrogen treatment reverses these deficits. In the current study, we investigated the effects of menstrual cycle phase and oral contraceptives on verbal memory, as measured by the California Verbal Learning Test, in two groups of premenopausal women — 16 naturally cycling women and 20 current users of estrogen-based oral contraceptives (OCs). Naturally cycling women were assessed twice — once during the early follicular phase (Days 2-4) and once during the midluteal phase (Days 20-22) of the menstrual cycle. OC users were tested on the same cycle days, corresponding to inactive and active pill phases, respectively. We predicted that naturally cycling women would show improved verbal memory during the midluteal phase, when estradiol levels are high, compared with the follicular phase, when estradiol levels are low. We also predicted that OC users, who show no change in endogenous estradiol across the cycle, would show no change in verbal memory. Contrary to predictions, naturally cycling women showed no changes in verbal memory across the cycle, whereas OC users showed enhanced memory during the active pill phase (p < .05). None of the secondary cognitive outcome measures varied with cycle phase or OC use including measures of visuospatial memory, verbal fluency, visuospatial abilities, and attention. Overall, these results suggest that verbal memory performance in premenopausal women varies across the cycle with OC use, but does not vary systematically with changes in endogenous estradiol.     

Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis

ObjectiveTo compare the risk of idiopathic venous thromboembolism among women taking third generation oral contraceptives (with gestodene or desogestrel) with that among women taking oral contraceptives with levonorgestrel.DesignCohort and case-control analyses derived from the General Practice Research Database.SettingUK general practices, January 1993 to December 1999.ParticipantsWomen aged 15-39 taking third generation oral contraceptives or oral contraceptives with levonorgestrel.ResultsThe adjusted estimates of relative risk for venous thromboembolism associated with third generation oral contraceptives compared with oral contraceptives with levonorgestrel was 1.9 (95% confidence interval 1.3 to 2.8) in the cohort analysis and 2.3 (1.3 to 3.9) in the case-control study. The estimates for the two types of oral contraceptives were similar before and after the warning issued by the Committee on Safety of Medicines in October 1995. A shift away from the use of third generation oral contraceptives after the scare was more pronounced among younger women (who have a lower risk of venous thromboembolism) than among older women. Fewer cases of venous thromboembolism occurred in 1996 and later than would have been expected if the use of oral contraceptives had remained unchanged.ConclusionsThese findings are consistent with previously reported studies, which found that compared with oral contraceptives with levonorgestrel, third generation oral contraceptives are associated with around twice the risk of venous thromboembolism.     

Cellular composition of cervical smears in relation to the day of the menstrual cycle and the method of contraception

The influence of the day of the menstrual cycle and the method of contraception on the cellular composition of cervical smears was investigated. The percentage of unsatisfactory smears during the first four days of the cycle was understandably very high, leaving only 80% of the smears of sufficient quality for cytologic diagnosis. The percentage of smears of insufficient quality during the remainder of the cycle was significantly higher in women using oral hormonal contraceptives. The percentages of smears containing endocervical columnar cells, a criterion for judging smears to be of high quality, differed significantly among women using different modes of contraception. The highest percentage of smears without endocervical columnar cells was found in women using oral contraceptives; during the first half of the cycle in these women, smears were of higher quality than during the second half of the cycle. In women not practicing contraception or using nonhormonal methods of contraception, the differences in cellular composition during the cycle, though significant, were too small to be of practical importance. Women using oral contraceptives thus have an increased risk for a potential false-negative diagnosis because of the higher percentage of smears of unreliable quality taken in these women. In women using oral hormonal contraceptives, smears should be taken during the first half of the cycle because of the higher percentage of smears of high quality in that period.     

Studies of Carbohydrate and Lipid Metabolism in Women Developing Hypertension on Oral Contraceptives

Metabolic studies in 100 women developing hypertension on combined oestrogen-progestogen oral contraceptives have been compared with similar studies in normotensive women on oral contraceptives, matched for age and duration of contraceptive use, and in women not taking contraceptives.The metabolic changes known to be induced by oral contraceptives—impaired glucose tolerance, elevated blood pyruvate levels, and raised serum lipid concentrations—were found to be exaggerated in the matched hypertensive group, largely due to pronounced abnormalities in 33 subjects with diastolic blood pressures over 110 mm Hg.Women developing severe hypertension were older, more obese, and of higher parity than those with mild hypertension and there was a high incidence of previous toxaemia of pregnancy in the hypertensive group.The results show that in women on oral contraceptives changes in blood pressure and in metabolic functions tend to be correlated with one another, and are consistent with the hypothesis that oral contraception induces a primary biochemical effect whose expression in the individual is determined by intrinsic factors including genetic constitution, age, weight, and parity.     

Effect of Sex, Menstrual Cycle Phase, and Oral Contraceptive Use on Circadian Temperature Rhythms

The circadian rhythm of rectal temperature was continuously recorded over several consecutive days in young men and women on regular nocturnal sleep schedules. There were 50 men, 21 women with natural menstrual cycles [i.e., not taking oral contraceptives (OCs) (10 in the follicular phase and 11 in the luteal phase)], and 14 women using OCs (6 in the pseudofollicular phase and 8 in the pseudoluteal phase). Circadian phase and amplitude were estimated using a curve-fitting procedure, and temperature levels were determined from the raw data. A two-way analysis of variance (ANOVA) on the data from the four groups of women, with factors menstrual cycle phase (follicular, luteal) and OC use (yes, no), showed that temperature during sleep was lower during the follicular phase than during the luteal phase. Since waking temperatures were similar in the two phases, the circadian amplitude was also larger during the follicular phase. The lower follicular phase sleep temperature also resulted in a lower 24-h temperature during the follicular phase. The two-way ANOVA showed that temperature during sleep and 24-h temperature were lower in naturally cycling women than in women taking OCs. A one-way ANOVA on the temperature rhythm parameters from the five groups of subjects showed that the temperature rhythms of the men and of the naturally cycling women in the follicular phase were not significantly different. Both of these groups had lower temperatures during sleep, lower 24-h temperatures, and larger circadian amplitudes than the other groups. There were no significant differences in circadian phase among the five groups studied. In conclusion, menstrual cycle phase, OC use, and sex affect the amplitude and level, but not the phase, of the overt circadian temperature rhythm.     

Effect of Sex,Menstrual Cycle Phase,and Oral Contraceptive Use on Circadian Temperature Rhythms

The circadian rhythm of rectal temperature was continuously recorded over several consecutive days in young men and women on regular nocturnal sleep schedules. There were 50 men, 21 women with natural menstrual cycles [i.e., not taking oral contraceptives (OCs) (10 in the follicular phase and 11 in the luteal phase)], and 14 women using OCs (6 in the pseudofollicular phase and 8 in the pseudoluteal phase). Circadian phase and amplitude were estimated using a curve-fitting procedure, and temperature levels were determined from the raw data. A two-way analysis of variance (ANOVA) on the data from the four groups of women, with factors menstrual cycle phase (follicular, luteal) and OC use (yes, no), showed that temperature during sleep was lower during the follicular phase than during the luteal phase. Since waking temperatures were similar in the two phases, the circadian amplitude was also larger during the follicular phase. The lower follicular phase sleep temperature also resulted in a lower 24-h temperature during the follicular phase. The two-way ANOVA showed that temperature during sleep and 24-h temperature were lower in naturally cycling women than in women taking OCs. A one-way ANOVA on the temperature rhythm parameters from the five groups of subjects showed that the temperature rhythms of the men and of the naturally cycling women in the follicular phase were not significantly different. Both of these groups had lower temperatures during sleep, lower 24-h temperatures, and larger circadian amplitudes than the other groups. There were no significant differences in circadian phase among the five groups studied. In conclusion, menstrual cycle phase, OC use, and sex affect the amplitude and level, but not the phase, of the overt circadian temperature rhythm.     

Pregnancy induced hypertension: evidence for increased cell membrane permeability to sodium.

In a cross sectional study of 137 women of childbearing age (16-40) the effects of normal pregnancy, hypertensive pregnancy, and oral contraceptives on red cell electrolyte content and sodium efflux rates were examined and the results compared with values in a control group of normotensive, non-pregnant women. Efflux rate constants were significantly increased in normotensive pregnancy and in women taking oral contraceptives. This was associated with a significant increase in sodium permeability in the contraceptive group. A much larger increase in sodium permeability and efflux rate constant was seen in the hypertensive group. The results permit a hypothesis that the hormonal changes induced by pregnancy and oral contraceptives increase membrane permeability to sodium and stimulate sodium efflux. The rise in blood pressure associated with use of oral contraceptives may have a similar aetiology to that occurring in pregnancy induced hypertension.     

Influence of hormonal contraceptives on the pituitary response to LH/FSH-releasing hormone.

In the pre-ovulatory phase the absolute and relative LH increase was much greater than during the luteal phase and less pronounced in the early follicular phase of the normal cycle. FSH release was affected only during the pre-ovulatory period, where a retarded, 3- or 4-fold increase compared to basal levels was recorded. In the women taking oral contraceptives of the conventional type the first LH-RH test showed gonadotropin responses similar to those obtained during the luteal phase of the controls. The second test brought a significantly lower LH response, suggesting an increasing exogenous steroid inhibition at the pituitary level in the course of the therapeutic cycle. This inhibition seems to be reversed during the monthly tablet-free interval. A particularly small and retarded gonadotropin response was observed in patients taking Deposiston. These results are discussed as to their clinical significance.     

Oral contraceptive use and venous thromboembolism: absence of an effect of smoking.

We conducted a case-control study to test the hypothesis that women smokers who use oral contraceptives have an increased risk of developing venous thrombosis. Patients and controls were drawn from two sets of hospital patients already included in the Boston Collaborative Drug Surveillance Programme. Sixty patients with uncomplicated thromboembolism were matched with 180 controls with other diagnoses; all were premenopausal women taking oral contraceptives. Patients with conditions that might predispose to thromboembolism or be related to smoking were excluded. We found no association between smoking habits and thromboembolism. Similarly, we found no association between thromboembolism, smoking, and duration of oral contraceptive use. Thus we conclude that differences in fibrinolytic activity between smokers and non-smokers are not major factors in the aetiology of uncomplicated thromboembolism in women using oral contraceptives.     

Changed levels of endogenous sex steroids in women on oral contraceptives.

Serum and urinary levels of unconjugated testosterone, dihydrotestosterone, and oestradiol were measured by specific radioimmunoassays in 10 healthy women in the early follicular phase of their menstrual cycle and in nine healthy women taking oral contraceptives. The contraceptive group had testosterone levels 1-3 times higher and dihydrotestosterone levels two times higher than those in the controls. Serum oestradiol levels in the contraceptive group were much lower than those in the controls and similar to levels in postmenopausal women. The contraceptive group had about twice the urinary excretion of unconjugated (free) testosterone and dihydrotestosterone of the controls, but their excretion of unconjugated oestradiol was 2-7 times lower. The great increase in serum and urinary androgen concentrations, as well as the suppression of oestradiol, may be related to the antiovulatory effect of oral contraceptives.     

Thrombosis and Oral Contraceptives: Possible Predisposition

The coagulation factors and components of the fibrinolytic system were examined in 31 women with a previous history of phlebographically-verified thrombosis during the use of oral contraceptives of the combined type. Special attention was given to the histochemically-determined fibrinolytic activator content of the wall of biopsy specimens of superficial veins. None of the patients was taking contraceptives at the time of the investigation. Pathological changes, particularly in the fibrinolytic defence system, were found in most of the patients. They may be regarded as predisposed to thrombosis, and one might wonder whether these patients would sooner or later have had their thrombosis even if they had not used contraceptives. The concentration of antithrombin III was normal, indicating that this test is of no value for detecting patients predisposed to thrombosis, who should preferably not take oral contraceptives.     

Oestrogen containing oral contraceptives and antithrombin III activity

67 women taking oral contraceptives were studied and compared with a group of normal women not taking oral contraceptives. In the oral contraceptive group, 31 were taking Infecundin, a compound with high estrogen content, and 36 were taking Bisecurin, a compound with less estrogen. Basic anthithrombin 3 (AT3) activity, as well as serum AT3, was determined in the presence of .25 IU/ml of heparin which normally increases thrombin inactivation. A paradoxical decreased effect was obtained with heparin, more frequent in the Bisecurin group. The basic determination of AT3 showed a decrease in 6 of 29 women taking Infecundin but a decrease was noted in 13 of the 29 controls, except in 1 case. A fall in AT3 activity does not imply formation of intravascular clots but may be a factor if other disturbances are also present. The determination may serve as a screening method.     

Blood Pressure in Women Taking Oral Contraceptives

A controlled prospective survey of women taking oestrogen-progestogen oral contraceptives showed increases in mean systolic and diastolic blood pressure of 14·2 mm Hg and 8·5 mm Hg respectively after four years. The largest increases in individual cases were 36 mm Hg systolic and 20 mm Hg diastolic. Blood pressure returned to pretreatment levels within three months after oral contraceptives had been stopped. These changes in blood pressure were unrelated to the progestogenic potencies of the preparations being taken.