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Focus in this discussion of pulmonary embolism is on the following: risk factors (age, heredity and blood type, obesity, estrogen and oral contraceptive use/pregnancy, cardiovascular disease, cancer, and other risk factors); pathophysiology and presenting symptoms; laboratory procedures and findings (radiography, electrocardiography, lung scanning, and evaluation of lower extremity veins); treatment modalities (heparin therapy, thrombolysis, and surgery); and prevention. Pulmonary embolism may be the primary cause or a major contributory cause in as many as 200,000 deaths per year in the US. Most of these deaths occur in patients in whom the diagnosis is not suspected and, thus, not treated. The mortality rate for untreated pulmonary embolism is approximately 30%. 90% of patients survive the initial embolic event, but the correct diagnosis is made in no more than 2/3 of cases. Risk factors for the development of deep venous thrombosis are based upon the Virchow-Aschoff postulates, which include: trauma or disruption of the vein wall; stasis of blood flow in the veins; and increased coagulability of the blood. More than 85-90% of all pulmonary emboli originate from deep venous thromboses in the popliteal and femoral deep veins. Other important, although less frequent, sites of origin of venous thromboembolism include the pelvic veins, the renal and hepatic veins, the axillary veins in the upper extremities, and the right atrium. Accurate diagnosis and effective prevention and treatment depend on the clinician's awareness of risk factors for development of deep vein thrombosis. Estrogen may accelerate intimal proliferation in arteries and veins, and it may also increase permeability of venous vascular endothelium. The risk of thromboembolism increases as the dose of estrogen increases. Both pregnancy and oral contraceptive use significantly decrease venous tone and the velocity of blood flow in the calf of the leg. Appropriate treatment includes thrombolytic therapy for patients with massive pulmonary embolism, which results in hypotension or shock. Anticoagulant therapy with herapin followed by an oral anticoagulant is the primary treatment for most patients with submassive emboli in which there is less cardiovascular compromise. When thrombolytic therapy is used, it should always be followed by anticoagulant therapy. Prevention of primary or recurrent deep vein thrombosis is directed toward improving venous blood flow and reducing hypercoagulability.
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PMID:Pulmonary embolism: incidence, diagnosis, prevention, and treatment. 398 Feb 63

3 cases of women becoming hypertensive while taking oral contraceptives are presented. The first was a 35-year-old mother of 4 who had developed hypertensive kidney disease in her last pregnancy. Before contraception her blood pressure was 130/75; it rose to 140/80 in 3 months and 160/100 in 6 months after taking Ovariostat (2.5-mg lynestrenol and .075-mg mestranol, combined). 2 months after discontinuing usage her pressure was 140/80. The second was a 45-year-old mother of 2 whose pressure climbed from 120/70 to 180/120 within 3 months of starting Planor (2-mg norgestrienone and .05-mg ethinyl estradiol, combined), and fell to 130/80 3 weeks after discontinuing usage. The third was a 32-year-old woman with blood pressure of 120/70 before taking Ovaristat. Within 15 days her pressure was 170/90, accompanied by severe headaches. 1 month after discontinuing usage it returned to 120/70. The discussants mention several cases in their experience, and agree with the authors that women with hypertension in pregnancy, obesity, or diabetes should not be given the pill. Normal patients should be followed carefully and advised to keep a low salt diet and normal weight.
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PMID:[Arterial hypertension during treatment with estro-progestative drugs]. 515 54

In response to recent studies from India suggesting that malnutrition, as assessed by anthropometric indexes, affects metabolism of oral progestogens, this study administered a mini-pill containing .35 mg of norethindrone (NET) and combination pills containing 250 or 150 mcg of d-norgestrel (d-NG) and either 50 or 30 mcg ethinyl estradiol as a single dose for fasting women of high and low income. Blood samples were collected for up to 24 hours for NET and 80 hours for the combination pills. Pharmacokinetics were evaluated by a least-squares method. Anthropometric measurements were also made. Peak NET levels occurred within 1-2 hours; half-life of plasma NET was shorter among low income, malnourished women compared with high income, well-nourished women. A direct correlation between weight/height and half-life of the drug suggests that malnutrition enhanation rate and reduces NET's half-life. Peak levels for d-NG also were reached between 1 and 2 hours after dosing. In well-nourished women, the decline in plasma d-NG was tri-exponential; malnourished women showed a biphasic curve with a neglible alpha-phase. Therefore, the lower the nutrition status, the faster the plasma clearance of these 2 orally administered compounds. Studies inn rabbits designed to elucidate this connection showed a significant elevation in specific activities of liver microsomal glucuronyl transferase and cytochrome-p450 in undernourished compared with control animals. There was also an increase in the amount (but not affinity) of uterine progesterone receptors in undernourished animals. Another study of a small group of Thai and Indian women showed positive correlation between anthropometric indexes and post peak plasma NET levels; however, an obesity study of Thai women found no such correlation.
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PMID:Influence of nutritional status on pharmacokinetics of contraceptive progestogens. 637 30

After widespread publicity about major adverse reactions to oral contraceptive agents, combinations were tested that contained lower doses of sex steroids than had been used before. Among them, the combination of levonorgestrel, 150 micrograms, and ethinyl estradiol, 30 micrograms, was studied intensively. European studies exclusive of the British Isles were conducted on 3,733 patients through approximately 36,000 cycles. There were nine pregnancies, for a Pearl index of 0.3. Cycle regulation was excellent, with normalization of menstrual flow. Amenorrhea was reported in 2.3% or less of cycles. No serious side effects were reported. The decrease in estrogen dosage, usually accompanied by a decrease in the progestational component, has resulted in a decrease in reported thromboembolic disease. Factors still important are diabetes mellitus, hypertension, obesity and cigarette smoking.
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PMID:Clinical experience with a low-dose contraceptive agent. European studies. 640 3

The efficacy of oral contraceptives (OCs) is influenced by any factor that affects circulating blood levels of exogenous estrogen or progesterone or that interferes with their action at a cellular level. Inadvertent pregnancies are not uncommon in combined pill users, and are usually due to errors of tablet taking. Estrogen-progestogen combinations work mainly by hypothalamic suppression; basal plasma levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) are usually repressed and their cyclical surges eliminated. Progestogen-only formulations have much less effect on central control and depend more on effects on the cervical mucus, endometrium, and possibly tubal function. Significant increases in FSH and LH levels may occur in the pill-free week among combined pill users. Reduction in dosage of some newer preparations appears to reduce the margin of error and, in low-dose progestogen-only pills, progestogen may reach inadequate levels for contraceptive effect before the expected time of the next pill. Higher failure rates in the 1st rather than in subsequent treatment cycles are mainly due to user failure, but method failures also may be more common, possibly because hypothalamic suppression increases over the 1st few cycles. 3 studies on pituitary and ovarian function in women who deliberately missed pills at specific stages showed an increase in breakthrough ovulation. Other clinical factors which may affect pill efficacy included vomiting, diarrhea, changing to a lower dose formulation, obesity, and drug interaction, especially with the antituberculosis drug rifampicin, some anticonvulsants, and antibiotics. Breakthrough ovulation from drug interaction is more likely to occur when OCs are administered early or late in the cycle. Analogously, the most hazardous times to miss pills are at the beginning or end of a monthly course.
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PMID:Why do inadvertent pregnancies occur in oral contraceptive users? Effectiveness of oral contraceptive regimens and interfering factors. 641 29

A case of acute intestinal vascular necrosis in a 19-year-old user of oral contraceptives (OCs) is described, and hypotheses explaining the digestive complications of synthetic estrogens are reviewed. The patient had originally presented with a violent gastric pain that subsequently spread to the entire abdomen. An abrupt worsening of her condition involved cardiovascular collapse associated with a peritoneal syndrome, vomiting and dehydration, and hyperleukocytosis. Emergency opening of the peritoneum was followed by evacuation of a large quantity of fetid gas and alimentary debris, and observation of a completely necrosed stomach. A careful lavage of the entire intestinal cavity led to temporary improvement, but it became clear during an attempt at gastrectomy that further treatment would be unavailing and the patient died shortly thereafter. Estrogens were believed to be responsible for the digestive necrosis because it occurred in a young woman who had used an estrogen-rich OC for 3 years and who smoked; a hapatic biopsy confirmed the diagnosis. No traces of other risk factors such as hypertension, hyperlipidemia, diabetes, neoplasia, or obesity were observed. Recent publications indicate that OCs are responsible for a certain number of digestive problems, which may include acceleration of intestinal transit, severe diarrhea, rectorrhagia, ischemic or ulcerative colitis, intestinal infarct which is usually localized, and hepatocellular problems ranging from moderate hepatic insufficiency to malignant tumor and Budd-Chiari syndrome. OCs do not modify hemodynamic regimes, but they may cause elevation of fibrinogen and thrombin, diminution of antithrombin III acitivty, increased platelet adhesivity, and decreased fibrinolysis leading to hypercoagulability. These modifications in hemostasis occur in all OC users and are not statistically correlated with occurence of thrombotic accidents. OCs are probably responsible for parietal vascular lesions; experimental injection of synthetic estrogens is associated with both arterial and venous lesions. The most characteristic anomaly is at the level of the intima, with proliferation of smooth muscle cells and increased conjunctive tissue fibers associated with proliferation of the media or the endothelium. The absence of lipid deposits, the simultaneous appearance of arterial and venous lesions, and other evidence argues against and atheromatous origin of parietal lesions. A significant correlation has been found between high levels of anti-synthetic ethinyl estradiol antibodies and the presence of vascular lesions. It is hypothesized that these circulating immune complexes penetrate the vascular walls of OC users and produce lesions, which may depend on factors such as smoking.
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PMID:[Digestive complications of oral contraceptives: a case of extensive digestive necrosis in a young woman]. 647 54

With few exceptions, most epidemiologic studies do not show an excess relative risk of breast cancer associated with menopausal estrogen therapy. Other studies show a relationship of breast cancer to obesity, which is characterized by increased endogenous estrogen production. This study explored the possibility of an interaction between ponderosity and exogenous estrogen use in a case-control study of 113 postmenopausal breast cancer patients and pair-matched hospital control subjects. In this series, neither menopausal estrogen use nor relative weight were significantly associated with breast cancer risk. However, among estrogen users, the relative risk of breast cancer was strikingly influenced by the ponderosity of the subjects; the relative risk was 0.41 for women whose relative weight was less than the median, compared with 1.29 for those whose relative weight exceeded the median. The mean age was also examined at diagnosis in order to explore the potential of exogenous estrogen as a tumor promotor. The mean age at breast cancer diagnosis in estrogen users, 58.1 years, was significantly lower than in nonusers, 63 years. A significant linear relationship was found between age at diagnosis and body weight among estrogen users. Estrogen-treated women in the lowest tertile of body weight had the diagnosis of breast cancer made seven years earlier than those in the highest tertile of weight. There was no significant difference in the distribution of clinical stages at diagnosis between estrogen users and nonusers. These data suggest that relative body weight is an important modifier of the effect of exogenous estrogens on breast cancer biology.
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PMID:Estrogen use and breast cancer. Interaction with body mass. 682 58

411 patients suffering from endometrial carcinoma were seen at the Roswell Park Memorial Institure in Buffalo, New York, between 1970 and 1978. These patients were matched and compared with 338 controls having no neoplastic disease or neoplasms other than of the female genital tract. There was a significantly higher incidence of diabetes, hypertension, and obesity in the uterine cancer patients than in the controls. On the other hand, nulliparity or family history of uterine or other cancer could not be correlated with endometrial cancer in these patients. The control and cancer groups did not differ markedly in the use of estrogens for menopausal or gynecologic reasons. Estrogen use in oral contraceptives (OCs) and for uncertain or unknown reasons was higher in the control than in the cancer group. The uterine cancer group was slightly older (median age 64.2) than the control group (median age 59.7), but this difference is small and believed unlikely to account for the results described.
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PMID:Estrogens and endometrial cancer. 694 29

Estrogen has been used to induce a wide variety of tumors in various animal species but only the rabbit is reported to reliably develop endometrial carcinoma. Variables associated in humans with an increase susceptibility to endometrial adenocarcinoma include aging, obesity, liver diseases, polycystic ovary disease, and ovarian tumors. In women estrogen induces mitotic activity in the endometrium and promotes the proliferation of the endometrium. Current concern that estrogen replacement therapy in postmenopausal women may be associated with increased risk of endometrial adenocarcinoma is based on: 1) reports of increased incidence of the disease, and 2) epidemiologic studies associating estrogen administration with an increased risk of endometrial carcinoma. The author draws the following conclusions based on the existing data: 1) there is likely a small but significant increase in the risk of development of endometrial adenocarcinoma among menopausal women on estrogen replacement therapy; 2) the increase in risk appears to be greatest for women who do not have any of the constitutional stigmas that would ordinarily place them at higher risk for adenocarcinoma; 3) risk increases with increasing duration of therapy, probably following a latent period of undetermined duration; 4) risk increases with increasing dose of estrogen; 5) progestin administration likely affords some protection against the risk, but the potential risks of administering the hormonal equivalent of a combination oral contraceptive periodically to elderly women have yet to be examined carefully; and 6) careful surveillance of patient populations on estrogen replacement therapy may limit the risk of adenocarcinoma associated with estrogens to early, highly curable lesions. It is incorrect to assume that estrogen actually causes carcinoma of the endometrium; it more likely induces a precancerous hyperplastic state in a dose-related fashion and only certain individuals ultimately develop invasive carcinoma.
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PMID:Does estrogen cause adenocarcinoma of the endometrium? 701 37

Clinical and pathologic findings were compared in 43 postmenopausal endometrial carcinoma patients who had received exogenous estrogens prior to diagnosis and 79 similar patients unexposed to estrogens. Estrogen non-users were more likely to manifest lower parity, later menopause, obesity, hypertension, and diabetes, all of which have been considered to be constitutional risk factors for the development of endometrial carcinoma. Although estrogen users and non-users had similar extent of disease as judged by clinical stage, there was a tendency to more myometrial invasion in hysterectomy specimens from non-users, as well as greater frequency of unfavorable histologic types and grades of tumor. At short-term follow-up, more recurrences occurred in non-users, and this tendency appeared to be independent of clinical stage, histologic type, histologic grade, or modality of treatment. The significance of these and other observation to the determination of the risk-benefit ratio for estrogen administration is discussed.
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PMID:Endometrial carcinoma: clinical-pathologic comparison of cases in postmenopausal women receiving and not receiving exogenous estrogens. 738 46


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