General Practitioners Oral Contraception Study Research Articles

Is the oral contraceptive pill associated with fracture in later life?: New evidence from the Royal College of General Practitioners Oral Contraception Study

Background Several studies, including an earlier analysis from the Royal College of General Practitioners (RCGP) Oral Contraception Study, have suggested that ever users of oral contraceptives have an increased risk of fracture when compared with never users. In this paper, we examined a subset of women in the RCGP study living in Scotland to determine whether this risk has persisted. Study Design A nested case-control study was carried out using data collected prospectively for the RCGP Oral Contraception Study. Cases were women with a first ever diagnosis of fracture ( n=651), age-matched to two controls ( n=1302). Adjustments were made for smoking, social class and parity. Results There was not a significant association between ever use of oral contraception and fracture (adjusted odds ratio 1.05, 95% confidence interval 0.86–1.29), compared with never users. Neither were significant associations found between fracture and smoking, social class and parity. The findings did not vary materially with age or type of fracture. Conclusion Ever use of oral contraception was not associated with fracture in this study.

Pill Use Is Associated with Reductions in Overall Risk of Cancer and in Risk of Main Gynecologic Cancers

Ever-use of the pill had no adverse effect on the overall risk of cancer in the large cohort of British women participating in the Royal College of General Practitioners oral contraception study. Rather analyses of data reflecting as much as 36 years of observation indicate that ever-users of oral contraceptives had a 12% reduction in the risk of developing any cancer and a 29% reduction in the risk of developing cervical uterine or ovarian cancer. (Analyses of data from a subset of the cohort however revealed no association between ever-use and the risk of any cancer.) Long-term pill use was associated with elevated risks of some cancers and with reduced risks of others. Analyses of data from the U.S. Nurses Health Study another long-term cohort study confirm the inverse association between pill use and ovarian cancer risk; they also show that the risk of this disease is reduced among sterilized women and elevated among women who have used an IUD or are infertile. (excerpt)

Weight Change in Adult Life and Health Outcomes

To investigate the relationship between weight change in adult life and subsequent mortality and cancer incidence in women. In 1994 to 1995, all women (age range, 42 to 81) still under general practitioner observation in the United Kingdom's Royal College of General Practitioners Oral Contraception Study (n = 12,303) were sent a health survey asking about health and lifestyle issues, including current weight and weight at age 30. The main outcome measures were 6-year all-cause mortality and cancer incidence among different weight change deciles. Cox regression was used to calculate hazard ratios that were adjusted for: social class at recruitment, BMI at age 30, and age group, parity, smoking status, and hormone replacement therapy status in 1995. Women who had been obese at age 30 were more likely to die and significantly more likely to develop cancer in the 6 years after the health survey than non-obese respondents. Women reporting weight gains between age 30 and 1995 were significantly less likely to die during the 6 years after the health survey than those with a stable weight, whereas those with weight loss did not fare any better than those in the stable-weight group. Although obesity at young age was associated with subsequent mortality and cancer incidence, weight gain over a time period of 12 to 51 years appeared to be beneficial when compared with women with stable weight over the same time period. Further research is needed to confirm or refute our findings and to allow detailed examination of potential explanations for them.

The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: a review.

Invasive cervical cancer remains a leading cause of morbidity and mortality, especially among women in the developing world where screening is either deficient or absent. Of all agents linked to the causation of this disease, high-risk human papillomavirus (HPV) appears to be the strongest factor. However, not all women with HPV develop cervical cancer. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its tumorigenic effect on cervical tissue. Steroids are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of various genes. Although some earlier studies were reassuring as no increased incidence of cervical cancer was observed, subsequent research has shown a causative association, especially among long-term users. The role of steroids was further enhanced by the discovery of hormone receptors in cervical tissue. Some earlier studies of oral contraceptive steroids found no increased risk, even after controlling for other risk factors, including smoking and number of partners. However, prospective studies have shown a greater progression of dysplasia to carcinoma-in-situ with more than 6 years of oral steroid contraceptive use. Similar findings were also evident from other work, including the Royal College of General Practitioners Oral Contraception Study. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives showed a relative risk of 1.2 for invasive cancer in users of the long-acting progestational contraceptive, depo-medroxyprogesterone acetate. However, in users of more than 5 years duration, an estimate of 2.4 was reported. The upstream regulatory region (URR) of the HPV type 16 viral genome, mediates transcriptional control of the HPV genome and is thought to contain enhancer elements that are activated by steroid hormones. It has been shown that steroid hormones bind to specific glucorticoid-response elements within HPV-DNA. Experimental evidence has revealed that high-risk type HPV 16 are able to stimulate the development of vaginal and cervical squamous cell carcinomas in transgenic mice exposed to slow-release pellets of 17 beta-estradiol in the presence of human keratin-14 promoter. Squamous cell carcinomas developed in a multi-stage pathway only in transgenic mice and not in nontransgenic mice. The E6 oncoprotein of HPV 16 has been shown to bind to the p53 tumor suppressor gene and stimulate its degradation by a ubiquitin-dependent protease system. Steroid hormones are thought to increase the expression of the E6 and E7 HPV 16 oncogenes, which in turn bind to and degrade the p53 gene product, leading to apoptotic failure and carcinogenesis. However, the molecular basis of this remains to be proven.

The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: A review

Invasive cervical cancer remains a leading cause of morbidity and mortality, especially among women in the developing world where screening is either deficient or absent. Of all agents linked to the causation of this disease, high-risk human papillomavirus (HPV) appears to be the strongest factor. However, not all women with HPV develop cervical cancer. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its tumorigenic effect on cervical tissue. Steroids are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of various genes. Although some earlier studies were reassuring as no increased incidence of cervical cancer was observed, subsequent research has shown a causative association, especially among long-term users. The role of steroids was further enhanced by the discovery of hormone receptors in cervical tissue. Some earlier studies of oral contraceptive steroids found no increased risk, even after controlling for other risk factors, including smoking and number of partners. However, prospective studies have shown a greater progression of dysplasia to carcinoma-in-situ with more than 6 years of oral steroid contraceptive use. Similar findings were also evident from other work, including the Royal College of General Practitioners Oral Contraception Study. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives showed a relative risk of 1.2 for invasive cancer in users of the long-acting progestational contraceptive, depo-medroxyprogesterone acetate. However, in users of more than 5 years duration, an estimate of 2.4 was reported. The upstream regulatory region (URR) of the HPV type 16 viral genome, mediates transcriptional control of the HPV genome and is thought to contain enhancer elements that are activated by steroid hormones. It has been shown that steroid hormones bind to specific glucorticoid-response elements within HPV-DNA. Experimental evidence has revealed that high–risk type HPV 16 are able to stimulate the development of vaginal and cervical squamous cell carcinomas in transgenic mice exposed to slow-release pellets of 17 β-estradiol in the presence of human keratin-14 promoter. Squamous cell carcinomas developed in a multi-stage pathway only in transgenic mice and not in nontransgenic mice. The E6 oncoprotein of HPV 16 has been shown to bind to the p53 tumor suppressor gene and stimulate its degradation by a ubiquitin-dependent protease system. Steroid hormones are thought to increase the expression of the E6 and E7 HPV 16 oncogenes, which in turn bind to and degrade the p53 gene product, leading to apoptotic failure and carcinogenesis. However, the molecular basis of this remains to be proven.

Oral contraception and ear disease: findings in a large cohort study

A number of authors have suggested that oral contraceptives may increase the risk of certain ear diseases, especially otosclerosis and vestibular disorders, although the amount of published information on this topic is limited. We have analyzed the available data on ear disease in the Oxford-Family Planning Association contraceptive study that includes 17,032 women followed for periods of up to 26 years. No evidence of any adverse effect of oral contraceptives on ear disease was detected. A protective effect of oral contraceptives against wax in the ear has been described in the Royal College of General Practitioners oral contraception study. The amount of data available in the Oxford-Family Planning Association study was too small to permit confirmation or refutation of this finding.

Oral contraception and other factors in relation to hospital referral for fracture: Findings in a large cohort study

There is good evidence that estrogens and progestogens have an important effect on bone metabolism. This article explores the relationship between oral contraceptive (OC) use and fractures occurring at various sites among the 17,032 participants in the Oxford-Family Planning Association contraceptive study, which now includes information accumulated during 310,000 woman-years of observation between 1968 and 1994. In total, 1308 women suffered at least one fracture during the follow-up period, which was largely confined to premenopausal years. When all fractures were combined, there was a modest, but highly significant trend (p <0.001) of increasing risk with total duration of oral contraceptive use. In addition, there was statistically significant heterogeneity (p <0.01) when overall fracture rates were examined in relation to recency of oral contraceptive use during the premenopausal lifespan. The highest relative risk (1.3, 95% CI 1.1–1.5) was for current or recent oral contraceptive users; however, viewed as a whole, no clear pattern of risk was apparent. Examination of the data for individual fracture sites (including the lower end of the radius/ulna) did not provide any evidence of a protective effect of oral contraceptive use. These results are closely similar to those reported from the Royal College of General Practitioners Oral Contraception Study in 1993.

Cervical Intraepithelial Neoplasia in Jordan: A Ten Year Retrospective Cytoepidemiologic Study

Occurrence of cervical intraepithelial neoplasia (CIN) was studied in 10,659 females attending obstetric and gynecology clinics in Jordan. The frequency rate of intraepithelial neoplasia was 1.1% in 7743 Jordanian females and 2916 non-Jordanian residents of younger age during the period from 1982 to 1991 inclusive. The incidence rate in 2649 Jordanian females, selected because they attended only for routine checkup, was 49 per 100,000. There were 121 CIN cases which were graded into Grade I (21%), II (48%) and III (31%) respectively. Histological grading correlated with cytology in 70% of the cases while in the remaining 30%, cytologic underrating by one grade was noted; evidence against any overdiagnosis of CIN in our series. Study of the human papillomavirus (HPV) was outside the scope of this effort. However, circumcision in male partners and marital status were associated with a lower frequency of CIN. Age at marriage and average duration, parity, breast feeding, the contraceptive pill, socioeconomic status and menstrual disorders showed no relationship to the frequency of CIN in our patients. Any differences in the latter between Jordanian and non-Jordanian females are believed due to cultural factors. Conization in 27 cases proved effective at 30 months' follow-up. Occurrence of CIN in Jordanian females appears substantial although much lower than that seen in high incidence zones, while its incidence in the general female population remains to be determined. This study shows for the first time the value of Papanicolaou (Pap) smears in Jordanian females over 20 years of age with special emphasis on those over 35 years of age attending obstetric and gynecology clinics.

Oral contraceptive pill use and fractures in women: A prospective study

It has been suggested that use of the oral contraceptive pill by women confers protection against osteoporosis later in life. However, cross-sectional studies of bone density among pill users have yielded discrepant results. We therefore investigated the relationship between pill use and subsequent occurrence of fracture in a cohort of 46,000 women enrolled in the Royal College of General Practitioners Oral Contraception Study during 482,083 person-years of follow-up. Fracture risk was lower among multiparous women, nonsmokers, and those of lower socio-economic class. The risk of subsequent fractures among the women who had ever used the oral contraceptive pill was significantly greater than that among women who had never used it (relative risk 1.20,95% confidence intervals 1.08–1.34) after adjustment for these variables. When the analysis was confined to forearm fractures, no significant effect of pill use on fracture risk was detected. Although the study only includes limited observation of older women to date, these data do not support the hypothesis that pill use protects women against the occurrence of osteoporotic fractures in later life.

Mortality among oral contraceptive users: 20 year follow up of women in a cohort study.

To see whether the use of oral contraceptives influences mortality. Non-randomised cohort study of 17,032 women followed up on an annual basis for an average of nearly 16 years. 17 Family planning clinics in England and Scotland. Women recruited during 1968-74. At the time of recruitment each woman was aged 25-39, married, a white British subject, willing to participate, and either a current user of oral contraceptives or a current user of a diaphragm or intrauterine device (without previous exposure to the pill). Overall mortality and cause specific mortality. 238 Deaths occurred during the follow up period. The main analyses concerned women entering the study while using either oral contraceptives or a diaphragm or intrauterine device. The overall relative risk of death in the oral contraceptive users was 0.9 (95% confidence interval 0.7 to 1.2). Though the numbers of deaths were small in most individual disease categories, the trends observed were generally consistent with findings in other reports. Thus the relative risk of death in the oral contraceptive users was 4.9 (95% confidence interval 0.7 to 230) for cancer of the cervix, 3.3 (95% confidence interval 0.9 to 17.9) for ischaemic heart disease, and 0.4 (95% confidence interval 0.1 to 1.2) for ovarian cancer. There was a linear trend in the death rates from cervical cancer and ovarian cancer (in opposite directions) with total duration of oral contraceptive use. Death rates from breast cancer (relative risk 0.9; 95% confidence interval 0.5 to 1.4) and suicide and probable suicide (relative risk 1.1; 95% confidence interval 0.3 to 3.6) were much the same in the two contraceptive groups. In 1981 the relative risk of death in oral contraceptive users from circulatory diseases as a group was reported to be 4.2 (95% confidence interval 2.3 to 7.7) in the Royal College of General Practitioners oral contraception study. The corresponding relative risk in this study was only 1.5 (95% confidence interval 0.7 to 3.0). These findings contain no significant evidence of any overall effect of oral contraceptive use on mortality. None the less, only small numbers of deaths occurred during the study period and a significant adverse (or beneficial) overall effect might emerge in the future. Interestingly, the mortality from circulatory disease associated with oral contraceptive use was substantially less than that found in the Royal College of General Practitioners study.

Oral contraception, smoking and inflammatory bowel disease--findings in the Royal College of General Practitioners Oral Contraception Study.

Data from the Royal College of General Practitioners Oral Contraception Study have been examined to determine whether oral contraceptive use was associated with the development of Crohn's disease or ulcerative colitis. Over a 17 year period Crohn's disease developed in 42 women and ulcerative colitis in 78. The incidence of both diseases was greater in oral contraceptive users compared to non-users with the rate ratio for Crohn's disease being 1.7 (95% confidence limits, 0.88, 3.2) and for ulcerative colitis being 1.3 (95% confidence limits 0.82, 2.0). For both diseases incidence was unrelated to parity or social class, but women smoking at recruitment had a greater incidence of Crohn's disease (rate ratio 1.8, 95% confidence limits 0.93, 3.3) and a reduced incidence of ulcerative colitis (rate ratio 0.68, 95% confidence limits 0.41, 1.1). Although these results are based on small numbers and could be chance findings, they are consistent with other studies showing associations between oral contraceptive use, smoking and the development of Crohn's disease and ulcerative colitis.

FERTILITY AND FAMILY MORTALITY AMONG ORAL-CONTRACEPTIVE USERS

Royal College of General Practitioners Oral-Contraception Study Department of Medical Statistics and Epidemiology, London School of Hygiene and Tropical Medicine, WC1

MORTALITY AMONG WOMEN PARTICIPATING IN THE OXFORD/FAMILY PLANNING ASSOCIATION CONTRACEPTIVE STUDY

43 deaths are known to have occurred among the 17 032 participants in the Oxford/Family Planning Association contraceptive study up to the end of April, 1977. 9 deaths from cardiovascular causes have been observed among the women in the oral-contraceptive entry group (49 681 woman-years of observation) while no such deaths have been observed among the women who entered the study while using a diaphragm or an intrauterine device (39 146 woman-years of observation). These findings are consistent with the results presented in the accompanying report from the Royal College of General Practitioners Oral Contraception Study.