Hepatocellular adenoma and focal nodular hyperplasia after long-term use of danazol for endometriosis: a case report

Danazol, an inhibitor of pituitary gonadotropin with weak androgenic effect, is currently being used for the treatment of endometriosis. In contrast to other C17 alkylated anabolic steroids, it has been rarely associated with the occurrence of primary liver tumors. We present the case of a patient with endometriosis in whom a hepatocellular adenoma was discovered after 14 years of treatment with danazol for endometriosis. The patient showed no clinical signs of a liver tumor and it was only detected by ultrasonography and magnetic resonance imaging (MRI). When long-term danazol therapy is required, regular ultrasonography for monitoring and early tumor detection is recommended.     

Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case-control study

OBJECTIVE: A role of female hormones, including oral contraceptives, has been suggested in the etiology of focal nodular hyperplasia of the liver. There is, however, no epidemiologic quantification of this relationship. STUDY DESIGN: A hospital-based case-control study was conducted in Italy of 23 women with histologically confirmed focal nodular hyperplasia of the liver and 94 controls in the hospital for acute diseases. Odds ratios (ORs) were computed by use of multiple logistic regression models. RESULTS: Focal nodular hyperplasia was not associated with menstrual and reproductive factors. Ever oral contraceptive use was reported by 83% of cases and 59% of controls. The multivariate OR was 2.8 (95% confidence interval [CI], 0.8-9.4) for ever use, and 4.5 (95% CI, 1.2-16.9) for use > or = 3 years. The trend in risk with duration was statistically significant. CONCLUSIONS: This study confirms previous clinical observations, and provides a quantitative estimate of the association between use of oral contraceptives and focal nodular hyperplasia of the liver.     

Oral contraceptives improve lung mechanics

OBJECTIVE: To determine whether oral contraceptives affect lung mechanics. DESIGN: Open-label study. SETTING: Academic medical center. PATIENT(S): Thirty-six healthy nonsmoking women. INTERVENTION(S): Administration of an oral contraceptive containing ethinyl estradiol, 35 microg, and norgestimat, 250 microg for 6 months. MAIN OUTCOME MEASURE(S): Forced vital capacity; forced expiratory volume in 1 second; peak expiratory flow; and flow at large, medium, and small lung volumes. RESULT(S): At 6 months, all forced expiratory flow and volume had increased significantly (from 6.5% to 15%). Flows at small lung volumes especially increased. CONCLUSION(S): Combination oral contraceptives have a measurable effect on lung mechanics.     

Modern oral contraceptive use and benign liver tumors: the German Benign Liver Tumor Case-Control Study

Objective To analyze the association between oral contraceptive use and the risk of benign liver tumors.

Methods Two parallel case-control studies on hepatocellular adenoma and focal nodular hyperplasia. Collaborative study of 15 German liver centers. Cases defined by histology and compared with population controls.

Results Fifty-one hepatocellular adenoma and 143 focal nodular hyperplasia cases (women) were recruited between 1990 and 1997, and compared to 240 population controls with a recent abdominal imaging test. The frequency age-matched odds ratio was 1.25 (95% confidence interval (CI), 0.37–4.22) and 1.96 (95% CI, 0.85–4.57) for hepatocellular adenoma and focal nodular hyperplasia, respectively. For hepatocellular adenoma, there was neither a significantly increased risk with longer duration of oral contraceptive use, nor an association with time since first or last use. For focal nodular hyperplasia, however, a slightly increased odds ratio was found with longer duration of use and more recent last use.

Conclusion There is little evidence for an increased risk for hepatocellular adenoma in women using modern oral contraceptives. If there is a risk not detected by the limited study size, hepatocellular adenoma is an extremely rare, and focal nodular hyperplasia a rare, adverse effect potentially associated with long-term oral contraceptive use and likely to be without public health importance.     

Oral contraceptives and human papillomavirus infection in cervical intraepithelial neoplasia

Summary We report about 142 patients from whom colposcopically directed cervical punch biopsies were taken which showed condylomatous lesions with or without cervical intraepithelial neoplasia (CIN). Fiftysix (39.4%) of these women used oral contraceptives (OC) for at least two years before examination. We used DNA in situ hybridization on all biopsies for detection of human papillomavirus (HPV)-DNA. Among OC users a significant trend towards higher HPV infection rates in high grade CIN (odds ratio 2.9,P<0.05) was found, whereas non-users of oral contraceptives had the highest HPV infection rate in condylomatous lesions without CIN (odds ratio 0.5,P<0.05). Thus in OC users HPV infection was about 24 times more likely in CIN III as in condyloma, whilest among non-users the trend was the other way round (7-fold likelyhood of HPV positivity in condyloma compared to CIN III). Other known risk factors for cervical carcinoma did not influence HPV infection rates in either group.     

Oral contraceptives suppress cell proliferation and enhance apoptosis of eutopic endometrial tissue from patients with endometriosis

Objective: To evaluate the effects of administering combination oral contraceptives (COCs) to patients with endometriosis on the regulation of cell growth in the eutopic endometrium.

Design: Prospective study.

Setting: Research institute and clinical fertility center.

Patient(s): Thirteen women with untreated endometriosis and 13 controls.

Intervention(s): Biopsy specimens of the eutopic endometrium were obtained from all subjects. Apoptosis, cell proliferation, and Bcl-2 and Bax expression were examined at the epithelial and stromal levels in the eutopic endometrium from patients with endometriosis before and after 30 days of daily exposure to COCs and from controls.

Main Outcome Measure(s): Apoptotic cells were detected by using the dUTP nick-end labeling assay; Ki-67, Bcl-2, and Bax expressions were assessed by using immunohistochemical techniques.

Result(s): After exposure to COCs, apoptosis was significantly increased in the eutopic endometrium compared with before COC administration, both at epithelial and stromal levels. Cell proliferation was significantly lowered by COCs.

Conclusion(s): COCs showed a positive effect on patients with endometriosis by down-regulating cell proliferation and enhancing apoptosis in the eutopic endometrium.     

Focal nodular hyperplasia of the liver and oral contraceptives.

The increased incidence of liver tumors in women of childbearing age who have been using oral contraceptives for many years suggests an environmental causation. The causative agent may be the steroidal oral contraceptives. Two lesions are recognized: focal nodular hyperplasia and hepatic adenoma. This paper concentrates on focal nodular hyperplasia, with two cases added to the four previously described cases. It is postulated that the estrogen component causes vascular lesions characterized by myointimal hyperplasia and thrombosis, leading to infarct, necrosis, and subsequent nodular hepatic regeneration. The clinical feature highlighted is the long history of gastrointestinal disturbance associated with negative gastrointestinal investigation with the possible exception of cholelithiasis. It is suggested that gray-scale ultrasonography is an effective screening method that also aids in a definitive diagnosis. As these tumors are often incidental findings it is emphasized that the liver should always be inspected at laparoscopy. Ultimately, diagnosis by biopsy or excision is essential as it may well be possible to treat cases of focal nodular hyperplasia of the liver conservatively, once oral contraceptives have been discontinued.     

Liver adenoma and focal nodular hyperplasia associated with oral contraceptives.

We report the case of a woman, with a 15-year history of high-dosage oral contraceptive use, who came to our center for a gynecological screening. Elevated liver enzymes were detected in blood samples and an abdominal ultrasound showed a hypoechogenic nodular image of 8 cm in the right hepatic lobe of the liver. Routine examinations, including hepatitis B surface antigen, hepatitis C viral antibody and alpha-fetoprotein, were all negative. Imaging studies, including computerized tomography scan, magnetic resonance imaging, sulfur colloid gammagraphy and hepatic angiography, were performed and confirmed the presence of the lesion, detecting the characteristic central scar structure of focal nodular hyperplasia. Discontinuation of oral contraceptives and follow-up showed no change in lesion size so that a surgical approach was adopted in order to remove the hepatocellular carcinoma. Pathological findings confirmed focal nodular hyperplasia.     

Oral contraceptives use and weight gain in women with a Central European life-style

Objectives?The aim of the study was to check and present data on the relation between combined oral contraceptives (COC) use and body weight in young women living in Poland.

Methods?Observational study on the group of young women on COC and the control group of young women who never used COC. Candidates for study (145 women) and control (218 women) groups were recruited in selected gynecological clinics in Poland during the period of 1–31 January 2002 (with the use of randomization).

Results?Both groups (study and control) were almost identical in age, anthropometric characteristics, number of pregnancies and deliveries. On the basis of this investigation it was found that there was no relation between use of COC and weight gain. Observed (in both groups) weight gain in young women was most probably related rather to time-passing (patients were getting older). The higher risk for overweight and obesity was found in the group of young women who had already had problems with overweight in their childhood. and in the group of women with high weight gain during the first pregnancy.

Conclusion?COC use is not associated with weight gain in young women with a Central European life-style.     

Oral contraceptives and mortality from circulatory system diseases: an epidemiologic study in Taiwan

An epidemiological study on the association between oral contraceptive (OC) use and circulatory system disease (CSD) mortality undertaken in Taiwan by proxy interview of closest family members of 306 deceased cases, 305 deceased controls, and 611 healthy neighborhood controls indicated that the relative risk between the cases and health controls was 0.98 (0.62-1.54) and that between cases and health controls was 0.82 (0.56-1.21). Use of OC by Taiwanese women has not produced any overwhelming adverse effects on CSD mortality.     

Oral contraceptives and coronary heart disease: Modulation of glucose tolerance and plasma lipid risk factors by progestins

Widespread use of oral contraceptive formulations by women throughout their reproductive life has given rise to concerns about the effects of oral contraceptives on risk factors for coronary heart disease. Oral contraceptive-induced changes in both carbohydrate and lipoprotein risk factors may contribute to an increased risk of coronary heart disease. Carbohydrate and lipoprotein risk factors for coronary heart disease are reviewed, and oral contraceptive-induced changes in carbohydrate and lipoprotein metabolism, which may lead to altered risk status for coronary heart disease, are discussed. The importance of methodology in evaluating the results of studies assessing such oral contraceptive-induced changes is stressed. The role of progestins in influencing coronary heart disease risk factors is surveyed, and differences among progestins commonly used in oral contraceptive formulations are discussed. In addition, the effect of various combination oral contraceptives on risk factor status is outlined. Finally, the implications of available evidence for the selection of progestins for oral contraceptive formulations of the future are discussed. Current data indicate that medium- and low-fixed-dose oral contraceptive formulations containing estrogen/norethindrone acetate have less metabolic impact than do comparable levonorgestrel-containing formulations, including multiphasic formulations. Triphasic formulations may have less effect on coronary heart disease risk factors, although data are not yet conclusive. Novel progestins such as desogestrel may also have lesser effects on metabolic functions, but the reduced androgenicity of such compounds may expose women to an increased risk of estrogen-induced hypertriglyceridemia.     

Triphasic oral contraceptives: review and comparison of various regimens

OBJECTIVE: To review and compare the risk-benefit profile of triphasic oral contraceptives with that of low-dose monophasic oral contraceptives.DESIGN: Literature on currently marketed triphasics and monophasics.Patient(s): Healthy women of reproductive age.MAIN OUTCOME MEASURE(S): Comparison of the rationale for development, composition, mechanism, efficacy, menstrual cycle control, side effects, health benefits, and risk-benefit profile.RESULT(S): All triphasics contain ethinyl estradiol (0.025-0.040 mg/d) and one of several progestins in doses (0.05-1.0 mg/d) related to their relative potencies, which are substantially lower overall (total dose) than those in monophasics. The triphasics are highly efficacious. In general, menstrual cycle control and side effects are similar in both types, but triphasics containing the newer progestins (desogestrel, gestodene, and norgestimate) have better cycle control and a reduced incidence of androgenic side effects compared with those with norethindrone or levonorgestrel. Both triphasics and monophasics have minimal effects on carbohydrate and lipid metabolism and hemostasis parameters, and therefore comparable low risks of coronary heart disease. The health benefits of triphasics and monophasics are similar and include decreased incidence of unwanted and ectopic pregnancies, ovarian cysts, endometrial and ovarian cancers, benign breast disease, and acute pelvic inflammatory disease; less menstrual blood loss and iron deficiency anemia; and lower frequency of irregular bleeding and menorrhagia.CONCLUSION(S): The risk-benefit profiles of both triphasics and monophasics are favorable and similar.     

Importance and knowledge of oral contraceptives in antepartum, low-income, African American adolescents

STUDY OBJECTIVE: To assess motivation, sense of self-efficacy and knowledge of oral contraceptives (OC) in antepartum, African-American Adolescents and young adults following OC counseling. METHODS: Gravid African-American females, less than 25 years of age, receiving prenatal care at the Prentice Ambulatory Clinic at Northwestern Memorial Hospital were eligible for this study. Participants were enrolled after 34 weeks gestation, received one session of standardized OC counseling and then completed a series of questions regarding importance, confidence and knowledge of OCs. RESULTS: Forty-three adolescents and young adults participated in this study. Almost all participants agreed that it was important to plan their next pregnancy and to avoid unplanned pregnancies. On average, participants were extremely confident they could take a pill each day. Yet, while most were confident that they knew what to do if they missed one pill, only 37% actually knew what to do if they missed one pill. CONCLUSION: Despite high motivation and confidence in their ability to take OCs following pregnancy, many in this cohort did not fully understand the counseling that they had received. It is important for clinicians to bear in mind that patients may express motivation and confidence about using OCs, but still lack knowledge of the more complex and critical aspects of OC use. Additional education and support are needed in high-risk populations to ensure effective contraceptive knowledge.     

A rare form of benign tumor of the liver possibly related to the use of oral contraceptives: focal pediculated nodular hyperplasia

Following a recent case, the authors review the literature of hepatic nodular hyperplasia. The incidence of this condition increases regularly with the consumption of oestrogens. They attempt to define the methods of detection for patients at highest risk. Without exaggerating the incidence of this complication of oral contraceptives, the authors believe that it will become increasingly more common than the vascular complications which, although frequently discussed, are relatively rare.     

Influence of oral contraceptives on drug therapy

Interferences between drugs and oral contraceptives are considered to alter pharmacokinetics and thus the efficacy of steroidal hormones. It should be noted, however, that steroids can also modify the metabolism and pharmakodynamic effects of various substances. To the present knowledge, phase I (i.e., oxidation, demethylation) and phase II reactions (conjugation) are concerned. Drugs sharing those enzymatic systems with oral contraceptives experience either an increase in bioavailability by inhibition of oxidative metabolism or undergo accelerated elimination by induced conjugation. Such interaction may be of practical interest in subjects who take oral contraceptives and are simultaneously treated with antidepressants, anti hypertensives, insulin, synthetic glucocorticoids, theophylline, and caffeine.     

不同方法治疗子宫内膜单纯性增生的疗效观察

目的:比较口服孕激素、口服避孕药及左炔诺孕酮宫内缓释系统(LNGIUS)治疗子宫内膜单纯性增生的疗效,进而对3种治疗方法进行评价。方法:前瞻性研究2010年8月至2013年6月在山东大学齐鲁医院门诊及住院收治的50岁以下、病理结果证实为子宫内膜单纯性增生的243例患者。将患者随机分为3组(每组各81例),分别接受口服孕激素(A组)、口服避孕药(B组)及LNG-IUS(C组)治疗6个月。治疗后每3个月取患者子宫内膜行病理检查,观察治疗后的病理结果。结果:治疗6个月时,口服孕激素组(A组)、口服避孕药组(B组)、LNG-IUS组(C组)的病理缓解率分别为97.5%、96.3%和100%,3组比较,无显著差异(P0.05);治疗期间,3组的突破性出血发生率分别为16.0%、6.1%和22.2%,差异显著(P0.025);体重质量增加发生率分别为51.9%、6.1%和4.9%,差异显著(P0.005);恶心呕吐发生率分别为7.4%、4.9%和2.5%,差异无统计学意义(P0.05)。3组患者均未出现血栓形成、头晕乏力、肝酶升高等不良反应。结论:对50岁以下的子宫内膜单纯性增生患者,口服孕激素、口服避孕药或左炔诺孕酮宫内缓释系统方法均可为首选。治疗方式的选择应取决于患者的依从性、身体一般状况及对药物副反应的耐受程度等。     

Oral contraceptives and clinical recurrence of human papillomavirus lesions and cervical intraepithelial neoplasia following treatment.

OBJECTIVE: To evaluate the effect of oral contraceptive use on the recurrence rate of human papillomavirus (HPV) lesions and cervical intraepithelial neoplasia (CIN) following ablative or excisional procedures in a long-term follow-up. METHOD: The study was conducted with 650 oral contraceptive users presenting with HPV lesions and/or CIN, and 670 women who had these lesions but did not use oral contraceptives acted as controls. The participants underwent cytologic evaluations, colposcopy, and direct biopsy, followed by either ablative treatment by laser carbon dioxide vaporization or excision by a loop electrosurgical excision procedure or cold knife conization. They were then followed up for a minimum of 5 years. RESULTS: The recurrence rates did not differ statistically between the case and control groups. CONCLUSION: Oral contraceptive use was not found to increase the recurrence rate of HPV lesions and/or CIN after ablative or surgical treatment.     

Focal nodular hyperplasia of the liver

Twenty-four patients underwent biopsy or resection of the liver for focal nodular hyperplasia (FNH) at Memorial Sloan-Kettering Cancer Center from 1978 to 1988. Twenty-two of the patients were women. The mean age was 35 years. A history of antecedent oral contraceptive or conjugated estrogen (Premarin) use was obtained in 18 of 21 women. There were two men, aged 26 and 37 years; neither gave a history of hormone use. Most of the tumors were solitary (22 of 24) and located in the left lobe of the liver (17 of 22). Fifteen of the patients had a prior or simultaneous malignant lesion and six had other benign tumors. Most of the tumors were resected with a wedge or subsegment of liver (13 of 24). Four patients underwent segmentectomy and five required lobectomy for removal of the tumors. Two patients had an intraoperative biopsy only. The patients in whom the tumor was diagnosed preoperatively underwent computed tomography and arteriography routinely. Scintigraphy of the liver with sulfur colloid was obtained in only three patients, despite its distinct potential for nonoperative diagnosis of FNH.     

Risks and mechanisms of cardiovascular events in users of oral contraceptives

Three large British studies on the vascular effects of oral contraceptives have established that the risk of thrornboembolic episodes, both venous and arterial, rises with increasing estrogen dose. Two of these studies have also demonstrated a dose-dependent relationship between the progestogenic component of oral contraceptives and the risk of arterial disease, though not of venous events. In men, high levels of factor VII coagulant activity, VII_c, and plasma fibrinogen are associated with an increased risk for ischemic heart disease. In view of the dose-dependent relationship between estrogen and these two clotting factors, especially VII_c, it is likely that the effects of oral contraceptive usage on the risk for thromboembolism are mediated substantially through the level of coagulability. The relationship between the progestogenic component of oral contraceptives and the risk for arterial disease is probably related, at least in part, to the effects of progestogens on blood pressure.     

Combined oral contraceptives affect liver mitochondrial activity

Abstract

Objectives To examine liver mitochondrial function in women using combined oral contraceptives (COCs) containing ethinylestradiol.

Methods A breath test after oral administration of 1 mg/kg ¹³C-alpha-ketoisocaproic acid (¹³C-KICA) and 20 mg/kg L-leucine was performed twice: (i) in 15 women on day 14, 15, 16, 17 or 18 of COC intake, and between day 1 and 5 of the withdrawal bleeding; and (ii) in 15 regularly menstruating females not taking hormonal contraceptives: during the luteal phase, between the 18th and the 22nd day of the cycle, and again between day 1 and 5 of the menstruation.

Results In women on COCs the maximum ¹³C elimination in breath air (D_max) was higher (26.8 ± 1.6%/h) than during withdrawal bleeding (23.5 ± 1.2%/h; p = 0.012). The time to reach the D_max was similar on the two study days: 33.3 ± 2.4 min during the phase of pill intake vs. 37.0 ± 2.5 min during the pill-free interval. The one-hour cumulative breath ¹³C elimination was greater after two weeks of COC intake than during the withdrawal bleeding: 17.49 ± 1.03% vs. 15.32 ± 0.85% (p = 0.024). In the control group no menstrual cycle phase-dependent fluctuations in the results of the ¹³C-KICA breath test were observed.

Conclusion The metabolism of ¹³C-alpha-ketoisocaproic acid augments during the intake of COCs containing ethinylestradiol, reflecting enhanced liver mitochondrial metabolic activity.