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Long-term oral contraceptive use does not affect trabecular bone density.

To determine whether long-term exposure to exogenous estrogen in oral contraceptives influences trabecular bone mass in premenopausal women, we studied 25 closely matched, healthy, premenopausal women, who were recruited from an active obstetrics and gynecology practice. Eleven women had never used oral contraceptives, and 14 women had used oral contraceptives for a minimum of 67 months. All oral contraceptive users had used preparations that provided a minimum of 50 micrograms mestranol per day. Trabecular bone density was determined by quantitative single-energy computerized tomography of the L1-3 lumbar vertebral bodies. Trabecular bone density was similar for both the control group and the oral contraceptive users, 160.6 +/- 6.9 versus 161.2 +/- 7.4 mg/ml, respectively. The power to detect a 15% difference in bone density between these two samples was 0.87. We concluded that long-term, premenopausal oral contraceptive use has no effect on vertebral bone density.

Absorptiometry, Photon↗

Long-term effects of MPA on human progeny: intellectual development.

Tests of verbal and spatial ability were done on 450 boys and 537 girls in their late teens of whom 73 and 97, respectively, had been exposed in utero to MPA. Exposed boys achieved higher raw scores than controls on verbal and spatial tests but the differences were explained by their more favorable demographic and social characteristics. Exposed girls did not differ from controls. Although, mothers of exposed boys reported that their offspring talked and walked later than controls, our results support the hypothesis that intrauterine exposure to MPA at contraceptive doses has no long-term effect on intellectual development.

Adolescent↗

Endometrial endothelial cell proliferation in long-term users of subdermal levonorgestrel.

The aim of the present study was to quantify endothelial cell proliferation (a component of angiogenesis) using immunohistochemistry, in the endometrium of users of subdermal levonorgestrel (Norplant). It was postulated that the increased endometrial microvascular density seen in Norplant users, compared to normally cycling women, was associated with an increased rate of endothelial cell proliferation. The results, however, showed that the endometrial endothelial cell proliferative index of Norplant users (0.39 +/- 0.16%; mean +/- SEM) was significantly reduced compared to that seen in normally cycling women (8.99 +/- 1.64). At the same time, total numbers of endometrial endothelial cells per mm2 in Norplant users (317.40 +/- 13.88) were significantly higher than in normally cycling women (223.35 +/- 10.31). It is possible that in the endometrium with levonorgestrel use, there is either a reduced rate of regression of the blood vessels relative to the rest of the tissue, or there is a reduced rate of endothelial cell death or turnover. Peripheral oestrogen and progesterone concentrations, bleeding pattern over the previous 90 days, and the histological appearance of the endometrium did not appear to be associated with the endothelial cell proliferative index. The results suggest that subdermal levonorgestrel use affects the mechanisms that dictate the normal relationship between endometrial blood vessel growth and regression, and the surrounding non-vascular tissue.

Cell Count↗

Pregnancy following induced abortion: maternal morbidity, congenital abnormalities and neonatal death. Royal College of General Practitioners/Royal College of Obstetricians and Gynaecologists Joint Study.

In a prospective cohort study of the long-term sequelae of induced abortion, a comparison is made between a group of 6418 women who had an induced abortion (cases) and a control group of 8059 women recruited with an unplanned pregnancy which was not terminated with an induced abortion (controls). The present paper reports on 729 cases and 1754 controls who had a post-recruitment pregnancy. In general, prior induced abortion had no material effect on the rate of pregnancy-related morbidity, nor on the rate of congenital abnormalities and neonatal death in the offspring. There was, however, a significant difference in two specific conditions. In the post-index pregnancy in the cases there was an increased relative risk (RR 2.26) of the occurrence of urinary tract infection and a decreased risk (RR 0.25) of pregnancy-related anaemia.

Abortion, Induced↗

Long-term biobehavioral effects of maternal separation in the rat: consistent or confusing?

Over the last decades of research there has been increasing interest in endocrine and behavioral effects of postnatal environmental manipulations. A manipulation procedure that has been widely used to date is that of maternal separation. Many studies have demonstrated that, in the rat, a single or repeated separation of the pups from the mother leads to acute as well as long-term effects on endocrinology and behavior. However, reviewing the literature shows that contrary findings for almost all parameters investigated can be found. A possible explanation for this inconsistency may be the fact that maternal separation has become a collective term for a variety of extremely different experimental manipulations. Therefore, this review aims at evaluating typical effects of maternal separation in the laboratory rat by categorizing different experimental procedures. We concentrate in particular on longterm behavioral effects, although a brief summary of neuroendocrine effects is also provided. In addition, important methodological issues of maternal separation studies are discussed as a possible source for inconsistent findings.

Adaptation, Physiological↗

Iatrogenic bladder perforations: longterm followup of 65 patients.

BACKGROUND: We reviewed our experience with bladder perforations to better understand the causes of these injuries and to describe their management and its effect on longterm outcomes. STUDY DESIGN: Our bladder trauma database yielded 65 patients during a 12-year period, followed for a mean of 36 months, who had sustained iatrogenic bladder perforations. Endourologic procedures were excluded. Demographic data, surgical details, mechanism of injury, anatomic location, grading, diagnosis, management, and outcomes were assessed. RESULTS: Gynecologic procedures accounted for 40 perforations (61.5%), general surgical procedures for 17 (26.2%), and urologic procedures for 8 (12.3%). The type of gynecologic surgery included abdominal hysterectomy in 16 (40%), resection of a pelvic mass in 12 (30%), cesarean section in 10 (25%), and diagnostic laparoscopy in 2 (5%). Of the general surgical procedures, eight were for colon cancer (47.1%), six for diverticulitis (35.3%), and three for inflammatory bowel disease (17.6%); of the urologic injuries, six occurred during vaginal surgery and two during laparoscopy. Predisposing factors were identified in 52 patients (80%). Intraoperative urologic consultation was obtained in 63 of 65 patients, with prompt identification and repair. In two cases a concurrent left ureteral injury was identified and managed by reimplantation. The sole complication was a vesicovaginal fistula 2 months postoperatively, so the success rate for repair was 98.4%. CONCLUSIONS: Although infrequent, iatrogenic bladder perforations can occur during any pelvic, abdominal, or vaginal procedure. Prompt intraoperative recognition is paramount to ensure satisfactory outcomes. Adequate repair usually can be achieved simply by vesicorrhaphy, limiting unnecessary extravesical dissection. With this approach, morbidity can be minimized.

Colon↗

Breast cancer risk in relation to type of estrogen contained in oral contraceptives.

We report analyses designed to address the recent hypothesis that women who use combination-type OCs containing ethinylestradiol (EE) are at increased risk of breast cancer before age 45, if use of such OCs occurs prior to first term pregnancy (FTP). Our findings, based on data from 1679 cases and 1689 controls, 20-44 years of age, from the population-based Cancer and Steroid Hormone Study, are against the hypothesis. The relative risk of breast cancer by duration of exclusive use prior to FTP of OCs containing EE is estimated to be 1.0 (1-12 months EE use), 1.2 (13-48 months EE use), and 0.9 (49+ months EE use). There was no evidence of a latent effect. Among parous women with 49+ months exclusive use prior to FTP of EE-containing OCs, the relative risk of breast cancer was estimated as 0.9 (0-4 years after FTP) and 0.6 (5-9 years after FTP). Among nulliparous women with 49+ months exclusive use of EE-containing OCs, the relative risk of breast cancer was estimated as 1.0 (0-4 years since first use), 0.7 (5-9 years since first use), and 1.1 (10-14 years since first use). With regard to exclusive use of OCs containing mestranol, parous women who used such preparations long-term before their FTP showed no alteration of breast cancer risk, even 15 years or more after pregnancy. Nulliparous women with exclusive use of ME-containing OCs did show elevations in breast cancer risk, but the magnitude of risk in relation to duration of use and latent interval shows no pattern that suggests a cause-effect relationship.

Adult↗

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.

Adult↗

Mammary tumors and serum hormones in the bitch treated with medroxyprogesterone acetate or progesterone for four years.

After 4 years of a long-term contraceptive steroid safety study, the incidence and the histologic types of mammary dysplasia produced are shown to be similar in beagles treated with medroxyprogesterone acetate (medroxyprogesterone) or progesterone. Serum insulin, thyroid-stimulating hormone (TSH), triiodothyronine, growth hormone, prolactin, 17 beta-estradiol, progesterone, and cortisol were determined by radioimmunoassay on samples collected after 45 months of treatment. Serum growth hormone and insulin concentrations were elevated in a dose-related manner in both treatment groups. Levels of triiodothyronine, cortisol, and 17 beta-estradiol (medroxyprogesterone only) were lowered. TSH and prolactin concentrations were not changed. Pituitary-gonadal hormone interaction in the pathogenesis of mammary neoplasia of the dog is discussed. Prolonged treatment of beagles with doses of progesterone or medroxyprogesterone 1 to 25 times the human contraceptive dose or luteal phase (dog) levels, respectively, results in a dose-related incidence of mammary nodules.

Adenoma↗

Forearm bone density in users of Depo-Provera as a contraceptive method.

OBJECTIVE: To determine the influence of depot medroxyprogesterone acetate (MPA) on bone mineral density when used as a contraceptive method. DESIGN: Cross-sectional study. SETTING: Academic tertiary-care hospital. PATIENT(S): Fifty premenopausal women who had used depot MPA as a contraceptive method for > or =1 year and 50 women who had never used hormonal contraceptive methods. INTERVENTION(S): Bone mineral density was evaluated at the midshaft and at the distal radius of the nondominant forearm using single x-ray absorptiometry. MAIN OUTCOME MEASURE(S): Bone mineral density. RESULT(S): Bone mineral density at the midshaft of the forearm was lower in depot MPA users than in women who had never used hormonal contraceptive methods, but the difference was not statistically significant. At the distal portion, bone mineral density was significantly lower in the study group. The duration of depot MPA use was not related to bone mineral density. CONCLUSION(S): Women > or =35 years of age presented with a lower bone mineral density only at the distal portion of the forearm after the use of depot MPA for > or =1 year. However, this decrease was not related to the duration of depot MPA use. It is not possible to conclude that women who use depot MPA are at risk of osteoporosis.

Adult↗

Problems in evaluating chronic toxicity of contraceptive steroids in dogs.

The long-term effects of oral contraceptive steroids including a combination of norethindrone and ethynylestradiol, a sequential regimen of dimethisterone and ethynylestradiol, and daily administration of megestrol acetate were studied in female beagle dogs at dose levels of 1, 10, or 25 times the projected human dose levels. The major findings included cystic endometrial hyperplasia and pyometra requiring hysterectomies and alopecia for the norethindrone-ethynylestradiol and dimethisterone-ethynylestradiol treated dogs. These groups did not have accentuated mammary development or treatment-related hyperplastic or neoplastic changes. For dogs given dimethisterone-ethynylestradiol, numerous acne-like lesions occurred in the skin of the mammary areas. Dogs given the higher dose levels of megestrol acetate had marked mammary stimulation, hyperplastic and neoplastic changes in the mammary glands, and clinical and pathologic changes typical of diabetes mellitus. Mammary changes of nodular hyperplasia, benign mixed tumor, and adenocarcinoma appeared as distinct entities although constant and intense mammary stimulation may be a common denominator. Such mammary changes have not been found in long-term studies in monkeys or rats with megestrol acetate, and the relevance of the canine mammary changes to projecting potential tumorigenesis in women is questioned.

Alopecia↗

The influence of oral contraceptives on the risk of multiple sclerosis.

OBJECTIVE: To examine the risk of multiple sclerosis in users of combined oral contraceptives. DESIGN: Cohort study conducted between 1968 and 1996 using diagnostic data supplied by general practitioners SETTING: General practices throughout the United Kingdom. POPULATION: Royal College of General Practitioners' Oral Contraception Study cohort of initially 46,000 women recruited during the late 1960s. METHODS: Directly standardised incidence rates of multiple sclerosis were calculated for current, former and never-users of oral contraceptives using first ever cases of multiple sclerosis reported by the general practitioners. The standardisation variables were age, parity, social class and smoking history. Five-year survival rates in the different contraceptive groups were calculated using standard life table techniques. RESULTS: One hundred and fourteen first ever cases of multiple sclerosis had been reported by November 1996 during 564,000 woman-years of observation. The incidence rate in both current and former users was not materially different to that in never-users. Although based on limited evidence there was no suggestion that the five-year survival was affected by a woman's use of combined oral contraceptives. CONCLUSIONS: These findings do not suggest a greatly elevated risk of multiple sclerosis during, or after, use of combined oral contraceptives.

Adult↗

Sexual, reproductive and contraceptive risk factors for carcinoma-in-situ of the uterine cervix in Sydney.

Sexual, reproductive and contraceptive risk factors were investigated in a matched community-based case-control study of carcinoma-in-situ of the uterine cervix in Sydney. The risk was related strongly to the number of sexual partners: women who had had seven or more sexual partners in a lifetime had a six-fold increased risk compared with those with one or no partner. Early age at first sexual intercourse was also a risk factor, but this effect was reduced substantially after adjustment for the number of partners, with only a two-fold excess risk persisting for those with first intercourse before the age of 16 years as compared with those whose first sexual intercourse was at the age of 25 years or later. The long-term use of oral contraceptive agents was associated with an elevated risk (relative risk, 2.3 for more than six years of use); this effect was maintained for both oestrogen and progestogen doses. The risk increased with the number of induced abortions that had been undergone (relative risk, 2.2 for two or more abortions), but this effect was not statistically significant. A protective effect was found for women who had had a tubal ligation, for those who practised the rhythm method of birth control, and for women who breastfed. It is possible that these reduced risks may relate to unmeasured variables of life-style.

Adolescent↗