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Oestrogens are prescribed to women in two circumstances — as part of oral contraceptive preparations, or as postmenopausal hormone replacement therapy. Oestrogens may also be prescribed to men as part of the treatment of prostatic carcinoma or to lower plasma cholesterol. The relationship of oestrogens and, in the case of oral contraceptives, progestogens to cardiovascular disease has been studied in all these circumstances. This chapter will review the evidence of a relationship between these sex hormones and disease of the coronary or cerebral arteries. Oestrogens are also associated with venous thromboembolism but this will not be discussed here.

The most important target organs for combined oral contraceptive preparations are the anterior pituitary gland and the uterus. The long-term unopposed administration of estrogen produces endometrial hyperplasia and amenorrhea, which are unacceptable to most women and their medical advisors. Cyclic administration of progestogens in combination with the estrogen, however, produces predictable endometrial shedding and achieves a regular and acceptable bleeding pattern in most women. This was the main reason that the "delay of menses" test was adopted as the earliest clinical means of comparing the relative potencies of progestogens that were administered orally. Recently attempts have been made to compare the potency of progestogens on the other organ systems by the extrapolation of data derived from studies on the endometrium. This is inappropriate, inasmuch as the effects of progestogens and estrogens independently and in combination differ greatly depending on the target organ. In this article, the literature on this controversial subject is reviewed.The most important target organs for combined oral contraceptive preparations are the anterior pituitary gland and the uterus. The long term unopposed administration of estrogen produces endometrial hyperplasia and amenorrhea, which are unacceptable to most women and their medical advisors. Cyclic administration of progestogens in combination with the estrogen, however, produces predictable endometrial shedding and achieves a regular and acceptable bleeding pattern in most women. This was the main reason that the "delay of menses" test was adopted as the earliest clinical means of comparing the relative potencies of progestogens that were administered orally. Recently attempts have been made to compare the potency of progestogens on the other organ systems by the extrapolation of data derived from studies on the endometrium. This is inappropriate, inasmuch as the effects of progestogens and estrogens independently and in combination differ greatly depending on the target organ. In this article, the literature on the controversial subject is reviewed.

Oral contraceptives are the most popular birth control method for teenagers, yet many teens discontinue use of these contraceptives prematurely. The need to minimize any potential long-term medical complications from the use of contraceptive hormones must be balanced with the desirability of increasing acceptance of contraceptives by adolescents. There has been concern that the use of so-called "low-dose" estrogen preparations, although decreasing the likelihood of complications, may lead to side effects that make compliance less certain. The present study comparing two commonly used oral contraceptive preparations, one low dose, one conventional dose, tests the hypothesis that among adolescents an association exists between oral contraceptive side effects and compliance. Using a double-blind crossover method, 55 sexually active adolescent females received two months each of a preparation containing 35 micrograms ethinyl estradiol and 0.5 mg norethindrone and another containing 50 micrograms mestranol and 1.0 mg norethindrone. The 50-microgram preparation was associated with fewer side effects when administered during the first two months. No differences in side effects were noted in the latter two months, but there was a slight increase in weight gain when compared with the 35-microgram preparation. The most common side effect was inter-menstrual bleeding with the 35-microgram pill. There was no documented relationship between the occurrence of side effects and compliance.

Lo/Ovral is a combination oral contraceptive preparation. It acts mainly through the mechanism of gonadotropin suppression due to the estrogenic and progestational activity of the constituents. The predominant effect of estrogen is to inhibit secretion of FSH, while continued action of progesterone (related, but not equated to progestins) is to inhibit LH. Alterations in the genital tract, such as changes in the cervical mucus and the endometrium, may also contribute to the contraceptive effectiveness.

In recent years the use of the oral contraceptive preparations has provoked a considerable amount of discussion in the medical literature along with a vigorous reaction in the lay Press. Various side effects have been described and these have been in the main attributed to the oestrogen content of these preparations and, in particular, an increase in the incidence of venous and arterial thromboembolism in women taking oral contraceptives. (Inman, Vessey, Westerholm and Engelund, 1970; A Statement by the Committee on Safety of Drugs, 1970.) As a result of these findings the low oestrogen dosage is now being used as theincidence of serious thromboembolic phenomena is thereby significantly reduced. In addition to occlusive vascular lesions, there are numerous other complications, which in many instances require withdrawal of the drug, (Grant, 1968) and mood changes (Grant and Pryse-Davies, 1968) being two of the commoner troublesome features.

A method for classifying oral contraceptive preparations is presented. The comparative potency of estrogen and progestogen in any formulation is plotted on coordinate axes. The point representation for the formulation in question will thus reflect the overall potency, character, and types of possible side effects for a particular oral contraceptive. Illustrations show how to use this system for both contraceptive and infertility therapy.

Fifteen progestational steroids, including many of the compounds which are currently employed clinically as components of oral contraceptive preparations, were tested for ability to suppress pubertal ovulation in the rat. All of the compounds tested, except ethynodiol diacetate, inhibited initial ovulation. The steroids tested could be divided into two groups based upon their effects on uterine weight. The pregnanes and dimethisterone decreased uterine weight, while the nortestosterone derivatives increased the weight of the uterus. Compound effects on ovarian weight and body weight gain are also reported.

To determine the comparative metabolic effects of ethinyl estradiol and norgestrel in oral contraceptive preparations 45 women were administered these steroids in differing combinations for 21 days after which plasma protein levels were determined from blood samples. 11 women received .05 mg ethinyl estradiol alone daily and 15 received .25 mg d-norgestrel with it daily; 9 women received .03 mg ethinyl estrodiol daily and 10 women received .25 mg of d-norgestrel with it daily. The presence of norgestrel was found to significantly reduce the increased plasma protein concentration that results from estrogen administration (p less than .001). No significant difference was found between the .03- and .05-mg ethinyl estradiol doses in their effects in plasma protein levels with or without the norgestrel.

During treatment with estrogenprogestogen oral contraceptive preparations, blood levels of angiotensin II measured by radioimmunoassay were elevated to three times the normal value. This marked rise in blood angiotensin II occurred within five days of commencing treatment, persisted during oral contraceptive therapy for three months, and fell to normal levels after cessation of treatment. Plasma renin activity and renin substrate showed similar elevations during treatment, and were significantly correlated with the levels of blood angiotensin II. Plasma renin concentration fell significantly during treatment, to about 50% of the control value, and was inversely correlated with the blood angiotensin II level. These observations demonstrate that the estrogen-induced rises in plasma renin substrate and renin activity during contraceptive therapy result in high circulating levels of angiotensin II, and provide confirmatory evidence for the concept that the concomitant suppression of renin secretion i...

SummaryOne hundred and two women were treated for approximately 2 years with a low-dose progestogen-only oral contraceptive preparation (‘Exlutori’) containing 0.5 mg. lynestrenol per tablet. Therapy was continuous, without interruption of the cycle. The contraceptive reliability during the total of 2,421 cycles was 100%; side-effects, including breakthrough bleeding and spotting, were minimal – even in the first cycles of treatment.Serum alkaline phosphatase and SGOT-determinations in each patient after a year's treatment showed that liver function was undisturbed.

The Vitamin-B6 status of 309 women was investigated at the University of Ulm in Ulm Germany with the use of the pyrodoxine-dependent erythrocyte glutamate-oxaloacetate transaminase (EGOT)-activation test. 214 and 19 patients were taking combined and sequential oral contraceptive preparations respectively. 76 women were controls. 18.4% of the controls but 48.1% of the oral contraceptors had a deficient or marginal Vitamin-B6 status. Among the oral contraceptors neither dose of estrogen type of estrogen component nor duration of intake seemed to have importance in the determination of Vitamin-B6 status. When it occurred Vitamin-B6 deficiency tended to be more severe in the sequential-preparation group than in the combined-preparation group although the low number taking sequentials prevented the attainment of statistical significance. The data suggest pyrodoxine supplements should be routinely administered to oral contraceptors.

We have heard convincing evidence this morning of the alterations in plasma lipids induced by a broad range of oral contraceptive preparations. Because of the epidemiological association between atherosclerotic cardiovascular disease and hyperlipoproteinemia, hypertriglyceridemia as well as hypercholesterolemia (1), and the possibility that progestational agents may therefore limit the relative immunity from atherosclerosis enjoyed by premenopausal women, we have begun to explore the mechanism of the hypertriglyceridemia of oral contraceptive therapy. These studies, then, evaluate the altered balance between triglyceride (TG) input and removal which result in a raised plasma TG concentration in women given oral progestational agents.

Oral contraceptive preparations are now manufactured and prescribed on a large scale, and the public analyst has a duty to ensure that a chemically satisfactory product is supplied.A scheme has been devised that will enable all of the ingredients, both progestogenic and oestrogenic, of the preparations at present available in this country to be identified and assayed.The active ingredients are separated from the tablet excipients by solvent extraction, the solution is evaporated and the residue identified by using infrared spectrophotometry and thin-layer chromatography. Assay of the ingredients involves the use of ultraviolet spectrophotometry. A few exceptions were found to this general scheme and these have been successfully overcome by suitable modifications.

To determine the effect of oral contraceptives on mitotic indices in the peripheral blood leucocyte cultures of mothers and their progeny 70 women who had previously taken various oral contraceptive preparations (Ovulen-21 Anovlar-21 Gynovlar-21 Norinyl-1 Conovid-E Lyndiol-1 and Minovlar-21) were studied. Blood samples were collected at time of delivery from the mother and newborn and the percentage of mitoses was calculated from examination of 500 cells from each subject. No significant difference was found between the mitotic indices in treated subjects and appropriate controls. Providing the hormonal constituents of these pills are still effective after discontinuation of use for up to 60 months it is concluded that oral contraceptives have no appreciable adverse effect on the mitotic activity of peripheral blood cells.

Leucocyte counts of 408 male and 789 female blood donors aged 18-65 were studied at the Birmingham Regional Blood Transfusion Service. 2 separate 2.5 ml samples were taken from each donor at the end of the blood donation either in the morning or early afternoon. On each slide 200 cells were counted. Total and differential counts in males were the same at different ages. In females neutrophil and lymphocyte counts decreased with age particularly after menopause (neutrophil p less than .001 and lymphocytes p less than .01). Use of oral contraceptives was associated with an increase in the neutrophil count. With increasing parity increases in total cell and neutrophil counts were noted only in those not using the pill. Lymphocyte counts varied directly with hemoglobin concentration in women (p less than .001). In men the variation was less marked;y Monocyte counts were not altered. It is suggested that the age effects in women may be due to estrogens. The variation with hemoglobin levels is possibly explicable as due to the influence of nutritional and other environmental factors.

SummarySixteen women who had used a low-dose progestogen-only oral contraceptive preparation (‘Exluton’), containing 0.5 mg. lynestrenol per tablet, for periods of at least a year were studied. All had normal pregnancies after discontinuing the preparation and gave birth to healthy infants: 11 girls and 5 boys. No complications were found at subsequent routine examinations of the infants.

A young woman who developed a cerebral venous thrombosis shortly after commencement of an oral contraceptive preparation was subsequently found to have paroxysmal nocturnal haemoglobinuria. The aetiology of thrombotic complications in this condition is discussed, with particular reference to the additional risk factor of the contraceptive pill in this case.A case of a young women with paroxysmal nocturnal hemoglobin (PNH) who developed thrombosis of the cerebral veins after beginning a regimen of oral contraceptives is presented. She was 24 years old and presented with a 3-week history of frontal headache, neck stiffness, paraesthesiae of both arms, and weakness of the left leg. She had begun use of Microgynon 2 months before presentation, but had discontinued use when symptoms began. Hematological studies showed a shortened partial thromboplastin time, high fibrinogen and factor VIII levels, and prlonged euglobulin clot lysis time. Though this patient had a history of coagulation difficulties, it was not until after taking the estrogen-containing contraceptive preparation that PNH developed. The mechanism of thrombosis may be related to the liberation of thromboplastic material from hemolysed erythrocytes and to interaction between complement-sensitive platelets and complement components in plasma. It is suggested that the estrogen augmented the previously existing thrombotic condition in this patient, and that administration of estrogen-containing preparations should not occur in women with thrombotic disorders.

A study has been performed on the effect of Norinyl-1 and Ortho-Novin, two low-dose oral contraceptives, on blood-clotting factors. Ortho-Novin contains twice the amount of hormone as Norinyl-1. It was therefore possible to observe whether any changes detected were related to the dose of oestrogen-progestin combination. The women were tested in parallel with matched normal female controls and a group in the third trimester of pregnancy. Significant rises in factor VII and X levels were found with both low-dose preparations from the third month onwards. There was no difference between patients on Norinyl-1 and Ortho-Novin, and hence the clotting changes do not appear to be dose-dependent. The long-term effects on clotting factors of these low-dose oral contraceptive preparations remain to be investigated.

To deal with the confusion surrounding clinical acceptability of specific oral contraceptive preparations, a single set of forms for use in clinical research, together with a set of definitions, was recommended. Senior representatives of major pharmaceutical companies engaging in clinical trials in the United Kingdom were invited to cooperate. The Family Planning Research Unit of the University of Exeter was requested to provide facilities for meetings which began in 1972. An agreed set of forms has been designed and set of definitions has been developed to make the collection and interpretation of data more efficient. Organizations carrying out oral contraceptive clinical trials are invited to contact this unit. Forms, definitions, and further information will be provided on request.

5 female volunteers were studied who had been taking oral contraceptives containing 30 mcg of ethinylestradiol (Ovranette and Eugynon) to determine the effect of ascorbic acid in women receiving long-term oral contraceptive treatment. Clearly at all study periods (6 hours and 24 hours after ascorbic acid administration) the vitamin caused the plasma concentration of ethinylestradiol to rise; at 6 hours the mean percent increase was 16.3 and at 24 hours the increase was 47.6%. The dose of ascorbic acid given (1 gm) is that prescribed for prevention of colds. This drug interaction may allow reduction of amounts of ethinylestradiol in oral contraceptive preparations.

Eleven women were found to be hypertensive while taking oral contraceptive preparations (OCP) containing estrogen and gestagen. Three months after discontinuing medication, blood pressure was normal in 4 of the patients (group A), was intermittently elevated or labile in 2 cases (group B), and remained persistently above normal in 5 cases (group C). While taking OCP, all 11 patients had elevated plasma angiotensinogen (renin substrate). Plasma renin activity (PRA) was significantly increased by oral contraceptives in all 3 groups of patients. Plasma renin concentration (PRC) was profoundly suppressed in groups A and B while taking OCP. PRC was significantly reduced in hypertensive women of group C but not to the same extent as in groups A and B. After stopping OCP for 3 months, all patients had normal levels of renin substrate in plasma. PRA fell into the normal range in all groups after stopping OCP. PRC increased in all groups after stopping OCP but did not reach average normal levels in groups A and B....