Influence of augmented Hageman factor (Factor XII) titers on the cryoactivation of plasma prorenin in women using oral contraceptive agents.

Prolonged cold storage of plasma may induce the conversion of plasma prorenin (inactive renin) to renin. This phenomenon is exaggerated in oral contraceptive (OC) users; the titer of Hageman factor (HF, Factor XII) in OC users is higher than in nonusers. The present study relates these observations. The increment in plasma renin activity (PRA) during cold storage, as measured by generation of angiotensin I, correlated strongly with the initial plasma titer of HF. Increasing the HF titer of nonusers to that observed in OC users by addition of purified HF increased cold-induced PRA at least twofold, while reducing the plasma HF titer of OC users correspondingly decreased cold-induced PRA. Thus, in OC users, the enhanced conversion of plasma prorenin to renin during cold storage reflects the elevated plasma titer of HF.

PIP: Prolonged cold storage of plasma may induce the conversion of plasma prorenin (inactive renin) to renin. This phenomenon is exaggerated in oral contraceptive (OC) users; the titer of Hageman factor (HF, Factor 12) in OC users is higher than in nonusers. The present study relates these observations. The increment in plasma renin activity (PRA) during cold storage, as measured by generation of angiotensin I, correlated strongly with the initial plasma titer of HF. Increasing the HF titer of nonusers to that observed in OC users by the addition of purified HF increased cold-induced PRA at least 2-fold, while reducing the plasma HF titer of OC users correspondingly decreased cold-induced PRA. Thus, in OC users, the enhanced conversion of plasma prorenin to renin during cold storage reflects the elevated plasma titer of HF.

The pill and breast cancer: is there a connection?

PIP: Experts remain unsure if using oral contraceptives increases the chances that a woman will contract breast cancer. Although early studies generally indicated that there was no connection between pill usage and breast cancer, 3 recent longterm reports suggest otherwise. The Fertility and Maternal Health Drugs Advisory Committee of the Food and Drug Administration concluded that the new studies were inconclusive and recommended no changes to labeling of the pill. Known risk factors for breast cancer are a woman's age, menstrual history, reproductive experience, diet, benign breast disease, and family or personal history of breast cancer. In a reexamination of 1 of the studies, the risk of breast cancer was found to increase fourfold before age 54 for a subgroup of women--those who began menstruating before age 13, had no children, and had used the pill for more than 8 years. The 2nd study found that breast cancer risk by age 45 doubled for women using the pill for less than 10 years and quadrupled when used for at least 10 years. However, the overall risk did not increase according to length of pill usage. The 3rd study found a 200% increase in breast cancer among women aged 30-34 years who had previously used the pill, but no correlation in the overall results. Additional research following pill users over as long a period of time as possible should be undertaken. The National Cancer Institute will begin a 3-year study involving 2,000 American women in mid-1989 to examine roles of oral contraceptives, alcohol, and diet in breast cancer risk. It also will look at possible reasons for discrepancies found in the previous studies.^ieng

Oral contraceptive use and fibrocystic breast disease with special reference to its histopathology.

The relationship between use of oral contraceptives and fibrocystic breast disease was examined in a hospital-based case-control study undertaken in New Haven, Connecticut, from 1977 to 1979. Particular emphasis was placed on the extent of epithelial atypia and other histopathologic characteristics found in the biopsy specimens from the cases. Women who had ever used oral contraceptives were at a somewhat decreased risk for fibrocystic disease as a whole. Cases with high atypia and controls had similar patterns of oral contraceptive use, whereas cases with low and intermediate atypia had less oral contraceptive use than controls. Cases with intermediate atypia reported the lowest oral contraceptive use. Subjects with biopsy specimens exhibiting gross cysts, microscopic cysts, or papillomatosis were about 50% less likely to have used oral contraceptives than controls.

Oral contraceptives and breast cancer.

PIP: Changes in endogenous hormones at various times in life (e.g., early menarche, birth of the 1st child at an advanced maternal age, and late menopause) increase the changes of developing breast cancer. It is reasonable then to expect oral contraceptive (OC) use to increase the risk of breast cancer. It is difficult, however, to prove OC exposure has this effect due to changed OC use patterns plus OCs consist of many different hormones at various doses and compositions. Yet, OC use in the past (even more than 15 years of OC use) had not increased the risk of breast cancer in women of all combined age groups. 3 research groups have identified a small increase in overall risk in low risk women, but unidentified sources of bias or confounding could account for this increased risk. Some recent studies indicate an increased risk of breast cancer with duration of OC use, but the risk depends somewhat on dose of either the estrogen or the progestin. Nonetheless, these findings were weak and inconclusive. Other research shows long-term OC use increases the risk of breast cancer in just young women (under 45 years old). Future epidemiologic studies thus need to address increased breast cancer risk in women under 45 years old who used OCs for a long time. They need to look at whether the risk is due to early use and continues into older age or to longterm use at any time in just young women. Some studies should include women with and without various biological markers of susceptibility. Other studies should measure blood levels of estrogens and progestins in women using the same OCs. BAsed on the information now available, it would be unwise for physicians to warn women against using the highly effective OCs because they do prevent unwanted pregnancy and are protective against ovarian and endometrial cancer.^ieng

Oral contraceptive use and risk of gestational trophoblastic tumors.

BACKGROUND: Gestational trophoblastic disease refers to a spectrum of rare benign and malignant gynecologic disorders whose pathogenesis is not well understood. Recent studies from China and the United States have raised the hypothesis that long-term use of oral contraceptives before conception may increase the risk of gestational trophoblastic tumors. A multicenter case-control study of gestational trophoblastic tumors was undertaken to test this hypothesis. METHODS: Telephone interviews were conducted with 235 case patients, including 50 with gestational choriocarcinoma, and 413 control subjects matched on recentness of pregnancy, age at pregnancy, and area of residence. Relative risks (odds ratios) were computed by conditional logistic regression. Reported P values are two-sided. RESULTS: The relative risk estimate for ever having used oral contraceptives before the index pregnancy was 1.9 (95% confidence interval [CI] = 1.2-3.0), and the risk increased with duration of use (P for trend = .05). The estimate was highest for women who used oral contraceptives during the cycle in which they became pregnant (relative risk = 4.0; 95% CI=1.6-10), but there was no consistent pattern according to the time interval since last use. Separate analyses of choriocarcinoma and persistent mole yielded similar results, i.e., the relative risk estimates for oral contraceptive use were 2.2 (95% CI=0.8-6.4) and 1.8 (95% CI=1.0-3.0), respectively. Control for the number of sexual partners, which was independently associated with risk (P for trend = .05), did not materially change the results. CONCLUSIONS: This study, the largest to date, indicates that long duration of oral contraceptive use before conception increases the risk of gestational trophoblastic tumors. These findings may provide clues to the pathogenesis of this rare disease. Changes in use of oral contraceptives are not warranted, however, because the incidence attributable to oral contraceptive use is very low.

PIP: Recent studies in the US and China have suggested that long-term use of oral contraceptives (OCs) before conception increases the risk of gestational trophoblastic tumors. This association was investigated further in a study conducted at 8 US medical centers that specialize in the treatment of this gynecologic disorder. 235 cases, including 50 women with gestational choriocarcinoma, were matched with 413 controls on recentness of pregnancy, age at pregnancy, and area of residence. The relative risk estimate for ever-use of OCs before the index pregnancy was 1.9 (95% confidence interval [CI], 1.2-3.0) and the risk increased with duration of OC use. The relative risk was highest (4.0; 95% CI, 1.6-10.0) for women who used OCs during the cycle in which they became pregnant, but there was no consistent pattern according to the time interval since last OC use. The relative risks for choriocarcinoma and persistent mole associated with OC use were 2.2 (95% CI, 0.8-6.4) and 1.8 (95% CI, 1.0-3.0), respectively. This study, the largest to date, suggests that a long duration of OC use before conception does, indeed, increase the risk of gestational trophoblastic tumors.

Oral contraceptives as related to cancer and benign lesions of the breast.

We conducted a case-control study to search for any relationship between use of oral contraceptives and development of breast cancer or benign breast disease. Women less than 50 years old with these diseases were matched with 2 controls by age, race, religion, and hospital. Home interviews elicited information on oral contraceptive use and other host and environmental factors. The study population comprised 1,770 women, including 452 with breast cancer and 446 with benign breast disease. The relative risk of developing cancer or benign disease was measured by matched set and summary chi-square analyses. Although the relative risk of developing breast cancer among "ever-users" of oral contraceptives was 1.1, the risk among women using oral contraceptives for 2-4 years was 1.9 (significantly increased). This risk estimate reached 2.5 for the 2- to 4-year users if they were still taking oral contraceptives when entered into study. Moreover, prior biopsy for benign breast disease increased the cancer risk among long-term users by as much as 11-fold. The relative risk of breast cancer did not vary by age, interval since first use, earliest year of use, or interval since last use. These results could be interpreted to indicate that oral contraceptives did not induce breast cancer but may have accelerated the growth rate of preexisting breast cancer. The relative risk of developing benign breast disease among ever-users of oral contraceptives was 0.8 (significantly reduced); it decreased with longer duration of use until it reached 0.2 for women who took these hormones 8 years or more. The relative risk of benign breast was not affected by earliest year of use or interval since last use. We concluded that oral contraceptives reduced the incidence of benign breast disease, but that use of steroid hormones is ill-advised for women with already established benign breast disease.

PIP: A 3-year case-control study of 1770 women under age 49 from the San Francisco Bay area, who were admitted to area hospitals with newly diagnosed breast cancer or with benign noninflammatory breast lesions, is reported. There were 452 with breast cancer, 446 with benign breast disease, 433 with other medical conditions, and 439 with other surgical conditions. Detailed information was obtained concerning each subject's contraceptive practices, menstrual and obstetric experiences, hormone use, medical and surgical history, and family history of breast cancer. Those without breast disease were selected as suitable controls concerning risk factors. In all instances the risk of breast disease was compared between women who had or were using oral contraceptives and others. Current users of oral contraceptives were 16% of patients with breast cancer and 13% of control patients. Contraceptive users were 9% of patients with benign breast disease. 1/2 of those using oral contraceptives had done so for 2 years or less. Only 15% of those who used these drugs had done so for over 6 years. Relative risk for all age groups of developing breast cancer was estimated to be increased by 10% among oral contraceptive users. The risk was less in older patients. With duration of oral contraceptive use, risk was significant only for the 2-4 year users in whom it was increased twofold (p less than .01). Relative risks were the same with the different dose levels of contraceptive compounds. Among ever-users, cancer risk was much greater (six to elevenfold) for women with prior history of biopsy for benign breast disease, particularly among those who had used oral contraceptives more than 6 years. Other contraceptive measures are recommended for such women. Observation for long-term effects should include study of type-specific benign disease as related to use of the hormones and later development of cancer. It may be that use of oral contraceptives accelerated the growth rate of preexisting subclinical malignant lesions and that after 2 years these lesions reach the level of clinical recognition, all being diagnosed within the next 2 years.

Oral contraceptive use and fibrocystic breast disease of different histologic classifications.

The relationship between oral contraceptive (OC) use and occurrence of fibrocystic breast disease (FBD) of different histologic classifications was evaluated with data from a cohort study. Biopsy specimens from 232 women with FBD were classified into different atypia categories. In 96 matched pairs of OC users and nonusers, atypia scores were lower in users than in nonusers. Women without breast diseases (500 OC users and 500 nonusers) were sampled from the original cohort to form a two-stage "anamorphic" study with the 232 cases of FBD. The previously shown inverse association between OC use and FBD occurrence was present and increased with increased length of OC use. However, the "protective effect" of OC use did not vary for different histologic classifications of FBD. The findings from both paired and anamorphic analyses of the data are not consistent with the hypothesis that the use of OC is associated with decreased frequency only of FBD with minimal epithelial atypia.

Lack of an elevated risk of malignant melanoma in relation to oral contraceptive use.

Epidemiologic and laboratory data suggest an effect of oral contraceptives (OC) on the risk of malignant melanoma. This relationship was explored in a hospital-based case-control study of 160 women with malignant melanoma and 640 matched controls, all of whom were white and 20-59 years of age. A total of 63 cases (39%) had used OC compared with 270 controls (42%), yielding a relative risk estimate of 0.9 (95% confidence interval: 0.6-1.3). When a number of potential confounding factors were simultaneously controlled, the relative risk estimate was 0.8 (0.5-1.3). For use that lasted 5 or more years the estimate was 0.9 (0.5-1.6). The level of tumor invasion was not related to OC use. The evidence from this study suggests that OC, even when used for 5 or more years, do not increase the risk of malignant melanoma.

Effect of oral contraceptives on the mammary glands of Rhesus monkeys: a preliminary report.

PIP: To determine the relationship of oral contraceptive use and breast cancer, 96 rhesus monkeys were administered either Enovid-E (2.5 mg norethynodrel and .1 mg mestranol) or Ovulen (1 mg ethynodiol diacetate and .1 mg mestranol) cyclically for 5 years at doses of 1, 10 and 50 times the human dose. The animals' progress was compared with a control group of 32 monkeys. General physical and mammary gland examinations were conducted before treatment and monthly thereafter. During the 5 year study period none of the treated animals demonstrated clinical evidence of mammary gland lesions, no deaths from breast malignancy occurred, and no palpable breast nodules were found.^ieng

Her-2/neu and INT2 proto-oncogene amplification in malignant breast tumors in relation to reproductive factors and exposure to exogenous hormones.

In previous studies in southern Sweden, early use of oral contraceptives has been found to be accompanied by an increased risk of developing premenopausal breast cancer, and the tumors developing in these patients have shown a more aggressive behavior. In the present study, amplification of the proto-oncogenes Her-2/neu (also known as ERBB2) and INT2 was studied in primary tumor specimens from 72 premenopausal women and was related to starting age of oral contraceptive use and other reproductive risk factors. Amplification of Her-2/neu was more common among early oral contraceptive users (i.e., those starting at less than or equal to 20 years of age) than among nonusers or late users (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.6-16.7), whereas INT2 amplification did not differ significantly among those groups (OR, 0.9; 95% CI, 0.1-5.0). The likelihood of INT2 amplification was greater among users of progestins and those with a history of abortions before the first full-term pregnancy (OR, 9.0; 95% CI, 1.3-51.7; and OR, 18.6; 95% CI, 2.2-165.8, respectively). No significant relationships were found between proto-oncogene amplification and the variables of parity, age at first full-term pregnancy, or late abortion. The increased ORs persisted after adjustment for age at diagnosis and other risk factors. The findings suggest that the higher rate of Her-2/neu amplification among early oral contraceptive users is an effect of the oral contraceptive use per se rather than of the relative youth of the users. Moreover, the relationship between progestin use and early abortion and amplification of the INT2 gene is biologically plausible.

Parity and primary liver cancer among young women.

PIP: Researchers from the US National Cancer Institute compared data on 25-49 year old US women who died of primary liver cancer between 1985 and 1986 with data on age matched controls who died of causes other than liver conditions or oral contraceptive (OC) related conditions to determine the association between primary liver cancer and parity. Women who had experienced at least 1 live birth wear 1.9 times more likely to have died of primary liver cancer than were nulliparous women. The association was not significant (p=.22), however. The highest risks were among children with at least 6 children (odds ratio [OR]=2.9) and with 2 children (2.1). Further the risks were greater when the parents or spouse completed the questionnaire and the association almost reached significance (p=.07). This may have been due to parents and spouse providing more complete information than a friend or neighbor. The risks of developing primary liver cancer were higher among women who had never used OCs than they were among those who ever did. For example, the OR for never users past parity 2 was 3.6 compared with 1.3 for ever OC users. There was a higher risk associated with parity among long term OC users (=or 5 years) than with short-term OC users, however. The researchers concluded that since parity was positively associated with increased risk of primary liver cancer in the US (a low risk country), endogenous hormones may contribute to liver cancer development. The following facts add to this plausibility. Estrogen profiles of parous women are different from those of nulliparous women. Estrogen levels rise considerably during pregnancy. Estrogens alter liver metabolism. Pregnancy makes the body more defenseless against hepatitis and its sequelae. In low risk countries, the risk of primary liver cancer rises among women using exogenous hormones.^ieng

Early oral contraceptive use and breast cancer among premenopausal women: final report from a study in southern Sweden.

In southern Sweden during the 1960s, women began to use oral contraceptives (OCs) extensively at a young age. This case-control study investigates the relationship between the use of OCs and breast cancer development in women in southern Sweden diagnosed in the early 1980s. The risk for breast cancer after OC use among premenopausal women was modeled, after adjustment was made for age, age at menarche, and age at first full-term pregnancy or parity. Both the duration of OC use before 25 years of age and commencement of OC use at a young age were associated with a significant increase in the risk of breast cancer as well as a significant trend. The duration of OC use before the first full-term pregnancy was associated with an increased risk of breast cancer, but it did not show a significant trend. The total duration of OC use was weakly, but not significantly, associated with breast cancer development. The odds ratio for women starting OC use before 20 years of age was 5.8 [95% confidence interval (CI), 2.6-12.8]; for women using OCs for greater than 5 years before age 25, it was 5.3 (95% CI, 2.1-13.2); and for women using OCs for greater than or equal to 8 years before first full-term pregnancy, it was 2.0 (95% CI, 0.8-4.7). In multivariate analyses including the different measurements of OC use, only starting age of OC use was significantly associated with breast cancer. The exposure-response relationship between duration of OC use and risk of breast cancer depended on the age at first use of OCs. Given a fixed duration of OC use, the risk increased with younger starting age of OC use. The findings point to the importance of the early reproductive years as risk determinants for breast cancer after OC use.

Breast cancer epidemiology.

PIP: The various risk factors for breast cancer have been recognized for many years. A table lists these established breast cancer risk factors together with the approximate magnitude of the increase in risk associated with them. Breast cancer incidence rates increase with age throughout the life span in Western countries, although the rate of increase is greater up to age 50 years than after 50 years. Breast cancer is more common among women in upper rather than lower social classes, among women who never have been married, among women living in urban areas, among women living in the northern US than in the southern US, and among whites than blacks, at least among those over age 50. Women in North American and Northern European countries have the highest risk for breast cancer, women in Southern European and Latin American countries are at intermediate risk, and women in Africa and Asian countries have the lowest risk. Yet, rapid rates of increase in incident rates have been noted in recent years in many Asian, Central European, and some South American countries. The later the age at which a woman has her 1st full-term pregnancy, the higher her risk for breast cancer; the earlier the age at menarche and the later the age at menopause the higher the risk; and among women who have a premenopausal oophorectomy, the earlier the age at which this occurs the lower the risk. Among postmenopausal women, obesity is associated with an increase in risk. Lactation is negatively associated with subsequent breast cancer risk. Some current research is considering potential risk factors that have not been well studied in the past, including alcohol consumption, cigarette smoking, caffeine consumption, exposure to diethylstilbestrol (DES), emotional stress, exposure to electric power, and lack of physical activity. Other areas of current research reviewed here include radiation, mammographic parenchymal patterns, a high-fat diet, use of oral contraceptives (OCs), use of estrogen replacement therapy, and endogenous hormones. Cigarette smoking and caffeine consumption do not appear promising as potential etiologic agents. The studies of the DES-exposed women and of OC users suggest that the timing of exposure may be critical, since the possible effect of both these hormonal agents may be limited to specific time periods of rapid breast development. If such a critical period does not exist in postmenopausal women, then there may be little effect of hormones used at this time. Studies with long-term follow-up and that include long-term users are essential to studies of effects of hormones and other exposures.^ieng

Breast carcinoma etiological factors.

PIP: This review of breast carcinoma etiological factors considers the following: heritage; menses, marital state, and parity; breastfeeding; contraceptives; benign epithelial diseases of the breast; hormonal factors; cancer; iatrogenic factors; immunological factors; viral aspects of human breast cancer; dietary factors; and psychosomatic factors. Breast carcinoma is the most prevalent type of cancer in American women. 8% of American women can expect to be stricken with this disease. The rate in men is 1% that in women. The causes or reasons for a woman being afflicted with this disease remain equivocal. An abundance of evidence exists that the incidence of breast carcinoma varies greatly from 1 population to another throughout the world and that in most populations it is increasing. Due to earlier detection, improved medical care, and possible other factors, the death rate is not increasing as rapidly as the incidence rate. In general, the incidence is greatest in populations with the highest standards of living, such as those of Northwestern Europe and North America. Thus, a woman's heritage is usually a large factor in determining her low risk of developing mammary carcinoma. Heritage includes family, race, country of origin, religion, and any component of lifestyle that is firmly passed on from 1 generation to the next. These factors seem to have a great influence on the incidence of breast cancer, but there is little agreement on which components of heritage are most important and how they operate. Many publications report insignificant or no effect of menarchal age on breast cancer risk. Many reports mention breastfeeding along with other data in breast cancer etiological studies, but its influence on the disease seems to be insignificant. Possibly there is some synergistic influence, but available data is not strong enough to establish the direction. Many reports seem to suggest that oral contraceptives (OCs) increase risk in nulliparous women and may promote the growth of malignant neoplasia, but in parious women, if there is no incipient cancer present, OCs do not appear to increase risk and may even decrease risk. Benign epithelial lesions can be harbingers of breast carcinoma, but from the literature it is not easy to conclude the nature of the most risky lesions nor their relative risks. A familial or personal history of cancer in any location or tissue may increase the risk of breast cancer. Ionizing radiation, oophorectomy, hysterectomy, and hormone therapy are the principal iatrogenic factors that influence the incidence of breast cancer. Radiation is known to be a most powerful carcinogen and is probably responsible for more cancer than any other iatrogenic factor. None of the factors so far studied is of great importance singly, but in a situation where several act together, any one may appear to be significant.^ieng

On the epidemiology of oral contraceptives and disease.

PIP: Adverse and beneficial effects, especially with regard to mortality rates, of oral contraceptives (OC) are reviewed. In 1980 approximately 80 million women used OCs worldwide. OCs were first marketed in the United States in the 1960's, but by the 1980's low-dose combination pills with less estrogen and progesterone content became widespread along with the minipill, injectable preparations depo- medroxyprogesterone DMPA, and norethindrone containing capsules. Relative disease risk estimates are based on cohort studies and case- control studies. The Royal College of General Practitioners RCGP Oral Contraceptive Study of 1974 involved 46,000 women aged over 15 (50% were OC users, 50% were nonusers) the Oxford Family Planning Association Contraceptive Study of 1976 recruited 17,032 women aged 25-39, 56% of whom used OCs, and the Walnut Creek Contraceptive Drug Study of 1981 studied 16,638 women aged 18-54 of whom 28% were OC users and 33% were former users. A somewhat elevated mortality among ever-users of OCs in the order of 20% seems to be indicated by these studies mostly attributable to diseases of the circulatory system. Current OC use is also a risk factor in thrombotic stroke of the order of 4 or 5, but former use of OCs lowers the risk to 2. The effect of OC dose and formulation, duration of use, and predisposing factors on hemorrhagic and thrombotic stroke appears to be inconclusive with varying data from different studies. There is evidence for some increase in ischemic heart disease among current OC users, and also a 2-fold increase of myocardial infarction (MI) when smoking, serum cholesterol, and hypertension is taken into account, moreover higher estrogen dosage also contributes to a higher incidence of MI. There is also a 5-fold increase of venous thromboembolism among OC users induced by duration of use and estrogen potency, as OCs seem to promote atherogenesis, although the roles of progesterone and estrogen are conflicting. combination pills reduce the rate of endometrial cancer, provided protection against ovarian cancer, and do not seem to increase breast cancer incidence, although the relative risk of cervical cancer is elevated. Mortality risks with older OCs outweigh the benefits.^ieng

Relative sensitivity of postpartum gestational diabetic women to oral contraceptive agents and other metabolic stress.

Women who develop diabetes mellitus during pregnancy very often revert to normal carbohydrate metabolism after parturition. During this quiescent period, however, increased sensitivity to adverse metabolic stress is evident. Recurrence of impaired carbohydrate tolerance with greater frequency than in normal populations is observed following the administration of oral contraceptive agents, glucocorticoids, and certain placental hormones such as human chorionic somatomammotropin. Factors responsible for this vulnerability to adverse stress are unknown but, in part, may reside in subclinical defects in beta-cell function. Ultimately, the great majority of these individuals develop permanent disease, suggesting that diabetes initially manifested only during pregnancy is not transient but progresses to more severe forms later in life.

PIP: It has been observed that women who develop gestational diabetes mellitus, a deterioration in the carbohydrate tolerance, under the metabolic stress of pregnancy, often revert to normal carbohydrate metabolism following delivery. During the postpartum period and later, however, increased sensitivity to adverse metabolic stress is apparent. Later pregnancies will often cause the metabolic impairment to recur more severely. Permanent diabetes may result. In such subjects, impaired carbohydrate tolerance will occur more frequently than for the normal population following administration of OCs (oral contraceptives), glucocorticoids, and certain placental hormones. The literature of studies on the subject is searched to assess the etiology of such a phenomenon. It is believed that superimposition of an exogenous glucocorticoid stress on a preexisting condition produced by the pill may cause a defect in beta-cell function.

Contraception and diabetes.

PIP: The topic of diabetes and contraception should be better investigated. 1 survey of 300 insulin-dependent women showed that the glucose tolerance disturbance caused by OCs (oral contraceptives) is rarely serious. OCs do seem to precipitate or exacerbate cardiovascular disease in a minority of patients. Diabetic women using OCs are advised to have regular medical examinations, to use OCs for as short a period of time as possible, and to examine alternative methods of contraception. IUDs are not a suitable alternative. A high rate of IUD failure, i.e., pregnancy with the device in situ, occurs in diabetic women. It is believed that a metabolic abnormality of the diabetic endometrium may be responsible for this. Counseling of diabetic women and their husbands in the whole area of reproduction and contraception is necessary.^ieng

Osteoporosis in anorexia nervosa: the influence of peak bone density, bone loss, oral contraceptive use, and exercise.

Anorexia nervosa occurs early in life and predisposes to osteoporosis. Exercise may be protective. We asked: (1) Does failure to attain peak bone density contribute to the deficit in bone density? (2) Does oral contraceptive use protect against osteoporosis? (3) Is any protective effect of exercise confined to weight-bearing sites? Areal bone density (g/cm2) and body composition were measured by dual x-ray absorptiometry in 65 patients with anorexia nervosa and 52 controls. Comparing the 12 patients with primary amenorrhea and the 37 patients with secondary amenorrhea, bone density (mean +/- SEM) at the lumbar spine was 0.88 +/- 0.04 versus 1.06 +/- 0.03 (P = 0.001), respectively. Bone density at the femoral neck was 0.80 +/- 0.04 versus 0.92 +/- 0.03 (P < 0.05), respectively. These values differed before, but not after, adjusting for the respective duration of illness (73.0 +/- 10.3 versus 34.1 +/- 4.8 months, P < 0.001) and fat-free mass (31.6 +/- 1.3 versus 35.4 +/- 0.5 kg, P < 0.01). Bone density at the lumbar spine in the 16 patients with 31.8 +/- 8.3 months of contraceptive exposure was higher than in the 49 patients with no contraceptive exposure (1.14 +/- 0.05 versus 1.02 +/- 0.02 P < 0.02) but was lower than in controls (1.14 +/- 0.05 versus 1.27 +/- 1.02, P < 0.01). No protective effect of contraceptive exposure was detectable at the femoral neck.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: In Australia, a group of 65 patients with anorexia nervosa were studied. The diagnosis was based on DSM-III-R criteria. A total of 12 patients had primary amenorrhea. Of the 53 patients with secondary amenorrhea, 16 had taken oral contraceptives during a illness. A total of 19 patients were exercisers. 52 premenopausal healthy women volunteers with no illnesses known to affect bone were studied as the control group. Total-body and regional bone density (lumbar spine, L2-4, femoral neck, Ward's triangle, and intertrochanteric regions) were measured by dual x-ray absorptiometry. The 65 patients with anorexia nervosa had significantly lower bone density (lumber spine 1.05 +or- 0.02 gm/sq cm, femoral neck 0.91 +or- 0.02 gm/sq cm), weight (43.3 +or- 0.9 kg), fat mass (7.01 +or- 0.57 kg), and fat-free (lean) mass (34.89 +or- 0.53 kg) than controls (all p 0.001), even after adjustments for differences in age (24.4 +or- 1.0 years, and height, 162.5 +or- 0.8 cm). In the 12 patients with primary amenorrhea, the reduction in bone density at the lumbar spine and femoral neck was greater than the reduction at the corresponding sites in the 37 patients with secondary amenorrhea (p = 0.001 and p = 0.04, respectively). A total of 16 patients took oral contraceptives for 61 +or- 9% of the duration of their illness whose mean bone density at the lumbar spine was greater than in the 49 patients without contraceptive exposure (p 0.01) but less than in controls (p 0.01). The 19 patients who exercised vigorously had higher bone density at the proximal femoral sites than sedentary patients. Patients with anorexia nervosa commencing around puberty may be at greater risk for fractures because they have lower bone density. A protective effect of oral contraceptives was found at the spine; a protective effect of weight-bearing exercise was found at the proximal femur. Thus, estrogen replacement therapy may be an important therapeutic option in this illness.

Human serum binding capacity and affinity for 25-hydroxyergocalciferol and 25-hydroxycholecalciferol.

25-Hydroxyvitamin D-binding capacity and affinity were studied in human cord, adult, and maternal sera, and in sera from women receiving oral contraceptives, by in vitro satuaration analyses employing dextran-coated charcoal to adsorb unbound sterol. 25-Hydroxyergocalciferol and 25-hydroxycholecalciferol were equipotent in their ability to displace 3H 25-hydroxycholecalciferol from human serum binding sites. At 0C, the apparent dissociation constant for the serum binding of 25-hydroxycholecalciferol was low (Kd=8x 10-10M). Cord and adult sera had a similar 25-hydroxycholecalciferol binding capacity (1.8 x 10-6M), but the binding capacity of maternal sera and the sera from women receiving oral contraceptives was significantly higher. At physiological serum concentrations of 25-hydroxyvitamin D (5 x 10-8M), only 2-3% of human serum 25-hydroxyvitamin D-bindig sites are occupied.

PIP: Human serum binding capacity and affinity for 25-hydroxyergocalciferol and 25-hydroxycholecalciferol by human serum as well as the binding capacity and affinity of cord, adult, and maternal sera for 25-hydroxycholecalciferol were investigated by in vitro saturation analyses employing dextran-coated charcoal to absorb unbound sterol. The compounds were equipotent in their ability to displace tritiated 25-hydroxycholecalciferol from human serum binding sites. The dissociation constant at 0 degrees C for serum binding of 25-hydroxycholecalciferol was 8 X 10 (-10)M. Cord and adult sera had a similar 25-hydroxycholecalciferol binding capacity (1.8 X 10(-6)M) but the binding capacity of maternal sera and the sera from women receiving oral contraceptives was significantly higher (p less than .001). At physiological serum concentrations of 25-hydroxyvitamin D (5 X 10 (-8)M) only 2-3% of human serum 25-hydroxyvitamin D-binding sites were occupied.

Fibrinolysis, renin activity, and prorenin in normal women: effects of exercise and oral contraceptive medication.

PIP: 25 young women, 13 of whom on oral contraception (OC), were observed to study the effects of exercise and of OC on the blood fibrinolytic and renin systems. It appeared very clearly that exercise would activate the fibrinolytic system, and that renin activity was also stimulated, suggesting a relationship between the 2 systems. The connection between exercise, fibrinolysis and prorenin activity was evidenced by an exercise-induced drop in the proportion of inactive renin and fibrinolytic activity, and in the presence of contraceptive-induced activation of fibrinolysis. OC did not seem to raise plasma prorenin above the control value, but it did raise active-renin, especially late in the menstrual cycel.^ieng