Long-term effect of a continuous low dose of megestrol acetate on the genital organs and fertility of female rats.
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OBJECTIVE: Depot medroxyprogesterone acetate (DMPA), an injectable progestogen, is a widely used contraceptive acting primarily by inhibiting secretion of pituitary gonadotrophins, thus producing oestrogen deficiency. Cross-sectional and prospective studies in pre-menopausal women have shown DMPA use to be associated with reduced bone density, but bone density increases following discontinuation of the drug. Because fracture rates are low in pre-menopausal women, the principal concern arising from the effects of DMPA on bone is that there may be residual osteopenia in former users such that their post-menopausal fracture risk is increased. The present study addresses this question. DESIGN: Cross-sectional study of bone density in post-menopausal former users of DPMA and controls. SUBJECTS: Three hundred and forty-six normal post-menopausal women, of whom 34 had previously used DMPA. The median age at which DMPA use began was 41 years and the median duration of use was 3.0 years. MEASUREMENTS: Bone density was measured in the spine, proximal femur and total body by dual-energy, X-ray absorptiometry. RESULTS: There were no significant differences in bone density at any site between the women who had previously used DMPA and the others in the cohort. However, in those who had used DMPA for > 2 years there was a trend towards bone densities being lower in the former users, the differences from non-users being 1.6% in the lumbar spine (P = 0.6), 3.1% in the femoral neck (P = 0.4) and 0.5% in the total body (P = 0.8). There was no correlation between bone densities and the duration of DMPA use, the age at discontinuation of DMPA, or the time between DMPA discontinuation and the menopause. CONCLUSIONS: Any residual effects of depot medroxyprogesterone acetate use on post-menopausal bone density are small and therefore unlikely to have a substantial impact on fracture risk in the post-menopausal years.
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Among women in general the risk of breast cancer through 59 years of age does not appear to be affected appreciably by the use of oral contraceptives. Nonetheless, concern continues to be expressed about the effects of early age at first use, long-term duration of use, formulation, and a variety of other factors thought to influence breast cancer risk in the presence of oral contraception. A number of recent studies restricted to young women suggest that long-term use may increase the risk of disease occurring very early, but the present lack of consistent findings in well-conducted epidemiologic studies prevents any certain conclusion with regard to cause-and-effect. However, if an increased risk were indeed present, the most plausible interpretation is that long-term oral contraception promotes earlier clinical manifestation of breast cancer in some women while having no net impact on their lifetime risk of the disease.
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Combined oral contraceptives are undoubtedly popular. By the end of the 1980's, an estimated 63 million married women around the world were using this method of contraception. In Britain, perhaps 95% of all sexually active women have used the pill at some time before their 30th birthday. Commensurate with such widespread usage, huge amounts of money have been spent during the past 35 years investigating the health effects of this method of contraception. Since it appears that all of the potential risks and benefits have now been identified, can we divert resources from pill-related research into new areas of activity. While this proposition may be attractive to funding bodies, and other researchers competing for increasingly scarce resources, it ignores the fact that several major uncertainties remain concerning the safety of combined oral contraceptives.
Many studies have shown that oral contraceptive (OC) use increases a young woman's risk of breast cancer, although some studies suggest that the risk may be limited to recent use. The objective of this study was to determine what particular aspects of OC use could be important for breast cancer development at an early age in the cohort of women who had the opportunity to use OCs all of their reproductive life. The cases were first diagnosed with breast cancer at age 40 or younger between 1983 and 1988, and identified by the Los Angeles County Cancer Surveillance Program. Control subjects were individually matched to participating cases on birth date (within 36 months), race (white), parity (nulliparous versus parous), and neighborhood of residence. Detailed OC histories were obtained during in-person interviews with subjects. In general the risk estimates were small, and not statistically significant. Compared to no use, having used OCs for 12 years or more was associated with a modest non-significant elevated breast cancer risk with an odds ratio (OR) of 1.4 (95% confidence interval (CI) = 0.8-2.4). Long-term (12 years or more) users of high-dose estrogen pills had a non-significant 60% higher breast cancer risk than never users (CI = 0.9-3.2). Early use was associated with slightly higher ORs among young women (age < or =35), and among parous women. Recent use was associated with somewhat higher ORs among parous women and women above age 36. Analyses by stage, body weight, and family history yielded similar results. This study is consistent with a modest effect of early OC use on breast cancer risk in young women.
Maternal ageing is a very important factor in aneuploidy. It is associated with an increased risk of a liveborn trisomy, especially Down's syndrome, and with a dramatic increase in trisomic conceptions, the majority of which miscarry. A total of 585 volunteer couples who were planning pregnancies participated in a prospective study of reproduction. The couples answered extensive questionnaires and early pregnancy tests (day 28) were conducted each month. The number of years of contraceptive pill use was correlated with pregnancy outcome. Lowered rates of miscarriage were found with increased years of pill use. The cut-off point for this positive effect appeared to be 9 years. Use of oral contraceptives for > or = 9 years was associated with a spontaneous abortion rate of 11.3%, which is about half the rate (23%) which was found in couples who had not used the pill. However, the effect of pill taking was correlated with female age, and when age was examined as an independent factor, the reduction in miscarriage was only statistically significant in women > 30 years old, where the rate of abortion reduced from 28 to 7%. Because age-related aneuploidy in humans probably occurs as a direct or an indirect result of follicle depletion, it is proposed that the long-term use of the oral contraceptive pill protects against abortion due to aneuploidy by preserving the number of follicles.
We examined variations in human endometrial microvascular perfusion across one menstrual cycle in women who had undergone tubal ligation and did not report unusual menstruation. Endometrial red blood cell flux was monitored by laser Doppler fluxmetry via a fibreoptic probe atraumatically inserted transvaginally into the uterus of each of 13 conscious volunteers. The observations obtained have been compared with those previously reported from a matched control group of women [B.J. Gannon et al., Hum. Reprod., 12, 132-139 (1997)]. Women who had undergone tubal occlusion for sterilization exhibited greater endometrial perfusion during menstruation (cycle days 0-5), at the time of ovulation (cycle days 13-16) and in the late secretory phase (cycle days 23-28) than occurred in controls. In addition, vasomotion in the study group was lower than that in controls in the early and late secretory phase (cycle days 17-22 and 23-28). Tubal occlusion appeared to alter endometrial perfusion. It is possible that the reported menstrual changes in women following tubal ligation are a consequence of altered endometrial perfusion; a possible causative relationship is discussed.
A clinical review of the first 200 patients who attended the DES Referral Clinic at The Royal Women's Hospital, Melbourne, has been undertaken. To date, clear-cell adenocarcinoma has not been detected in patients attending the Clinic. Fifteen per cent of patients who allegedly were exposed in utero to diethylstilboestrol (DES) showed no clinical stigmata. Vaginal adenosis was found in 41% of patients. On its own, cytological examination of vaginal smears was found to be unreliable as routine screening for detection of adenosis. Painting of the cervix and vagina with Lugol's iodine proved to be a more reliable screening test. Colposcopy is recommended in all patients who are suspected of having been exposed in utero to DES.
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This review examines controversies concerning serious side effects of oral contraceptives. Current concerns about the pill are with either relatively small excess risks or with very long-term effects, which need not be small. The main outstanding questions are the effects on cardiovascular disease of lowering doses and the effects on breast cancer of oral contraceptive use at a young age. In the end, the possible effects on breast cancer incidence cause the most concern. It is argued that most epidemiologic studies are too small to reliably detect effects among particular subgroups and it is possibly too soon to know what the long-term effects of using oral contraceptives while young on breast cancer actually are. However, complacency is contraindicated.
A group of 205 women with endometrial carcinoma was matched for age, parity, and year of operation with a group of 205 women who had had hysterectomies for benign disease. In the former group, 32 patients had used conjugated estrogens, while in the latter group 12 had used this hormone, yielding a relative risk of 3.1 (P = 0.0008). Users of other forms of systemic estrogens showed similar elevations in relative risk. Relative risk was related to duration of use, progressing from no evidence of risk among those using the hormone for less than 5 years to an 11.5-fold greater risk for those using it for 10 years or more. Risk was also related to the strength of the medication. The relative risk for users of the 1.25-mg tablets was 12.7 as compared to a two- to fourfold greater risk among users of lesser strength tablets.
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