The use of herbal preparations to alleviate climacteric disorders and risk of postmenopausal breast cancer in a German case-control study.

BACKGROUND: The use of herbal preparations (HEP) to alleviate climacteric disorders is expected to increase as women seek alternatives to menopausal hormone therapy to avoid the associated breast cancer risk. Data are sparse on the long-term effects of HEP containing phytoestrogens and black cohosh on breast cancer risk. METHODS: Within a German case-control study, associations between patterns of HEP use and incident breast cancer were investigated in 10,121 postmenopausal women (3,464 cases, 6,657 controls). Information on HEP use was collected in face-to-face interviews supported by a list of brand names. Multivariate logistic and polytomous regression analyses were done. FINDINGS: Ever use of HEP (9.9%) was inversely associated with invasive breast cancer [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.63-0.87] in a dose-dependent manner (OR, 0.96 per year of use; P = 0.03). Classes of HEP did not differ significantly (P(heterogeneity) = 0.81). Risks for invasive ductal (OR, 0.72; 95% CI, 0.60-0.87) and combined lobular/mixed/tubular tumors (OR, 0.76; 95% CI, 0.58-1.01) were similarly reduced by any HEP use but not for in situ carcinomas (1.34; 95% CI, 0.86-2.09). There were no substantial differences in associations of HEP use by estrogen receptor status (ER(+) OR, 0.74; 95% CI, 0.62-0.89; ER- OR, 0.68, 95% CI, 0.50-0.93) and progesterone receptor status of the tumor. INTERPRETATION: Our findings support the hypothesis that HEP use protects from invasive breast cancer in postmenopausal women. Among conceivable modes of action, those independent of estrogen receptor-mediated pathways seem to be involved (i.e., cytotoxicity, apoptosis).

Menopausal hormone therapy and risk of clinical breast cancer subtypes.

BACKGROUND: Breast cancer is a heterogeneous disease with subtypes that may vary in their etiologies. Menopausal hormone therapy has been associated more strongly with lobular and tubular than ductal histologic types and with tumors that are smaller, hormone receptor-positive, and of lower grade. At the same time, correlations have been observed between histology and clinical characteristics. To identify those tumor subtypes most strongly associated with hormone therapy use, it is necessary to disentangle these interrelationships. METHODS: Based on 3,464 postmenopausal breast cancer cases and 6,657 controls from the population-based Mammary carcinoma Risk factor Investigation study, we used polytomous logistic regression to evaluate associations between hormone therapy use and risk of invasive breast cancer subtypes. We assessed variations in risk for selected tumor characteristics among histologic and hormone receptor subtypes, both overall and for specific hormone therapy regimens. RESULTS: Lobular and mixed types showed less variation by prognostic factors than did ductal tumors. Current hormone therapy use had the strongest associations with prognostic variables in estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive ductal tumors and in lobular tumors regardless of ER/PR status, with little effect on ER/PR-negative ductal tumors. The observed associations varied minimally by hormone therapy type or regimen. CONCLUSION: Current hormone therapy use was associated with more favorable breast cancer characteristics for ductal tumors but had less effect on prognostic characteristics in women with lobular tumors. Both histologic type and estrogen receptor/progesterone receptor status seem to be important in explaining the role of hormone therapy in the etiology of breast cancer subtypes.

[Long-cycle treatment in oral contraception]. / Langzyklus bei Ovulationshemmern.

Surveys show that most women desire a change in their menstrual pattern in the sense that they would prefer less menstruations or even amenorrhea. On this behalf, there is no difference between women having spontaneous natural cycles and women taking the pill. The main reasons are less menstrual bleedings, better hygienic conditions, a better quality of life and less blood loss. In women wanting regular monthly periods, the opinion is dominant that suppression of menstrual bleedings is "unnatural". It is therefore primordial to inform women that contraceptive safety is even increased in users following the long-cycle principal and that a fertility decrease has not to be feared. The benefit of the long-cycle OC is a reduction of the hormonal fluctuations induced by the pill-free interval with its consecutive somatic and mental symptoms, as well as an increased contraceptive safety. The following cycle- and menstruation-dependent symptoms as listed as an indication for the long-cycle use: Endometriosis, hypermenorrhea, dysmenorrhea, hemorrhagic diathesis, uterine fibroma, polyzystic ovary syndrome, migraine due to estrogen-deficiency in the pill-free interval as well as premenstrual syndrome.

[Oral contraception - doses and way of administration]. / Hormonale Kontrazeption - Dosierung und Verabreichungsformen.

Since the correlation between the amount of Ethinylestradiol (EE) and the thromboembolic risk has been recognized, the development of new oral contraceptives (OC) has been characterized by a constant lowering of the EE dosage. The consecutive decrease of ovulation inhibition has been compensated by the introduction of potent progestagens. Therefore, the contraceptive safety has been maintained in presence of less side-effects. The effect of ultra-low-dose OC on acne and seborrhea remains beneficial. The effect of ultra-low-dose OC on bone is contradictory. Because there are fundamental differences between Estradiol and EE, the thromboembolic risk is not decreased by the parenteral administration of EE. In users of the contraceptive patch, it is even increased. EE is not bound at SHBG. Because of its Ethinyl group, the inactivation of EE occurs slowly. Therefore, EE reaches the liver in a low but constant concentration where it modifies many estrogen-dependent hepatic parameters significantly. One of these is hemostasis. It is generally accepted that such changes are responsible for the increased thromboembolic risk of the contraceptive patch and vaginal ring. A reduction of the hormone-free interval of the pill to 5 or 4 days results in a complete suppression of the ovarian function, a reliable ovulation inhibition and an increase of the contraceptive efficacy in spite of a reduction of the EE dosage to 20 microg or 15 microg.

[Contraception in adolescence and perimenopause]. / Kontrazeption zu Beginn und Ende der fertilen Lebensphase.

The risk-benefit-ratio of hormonal contraception (OC) is positive in adolescents as well as in women over 40 years of age if some essential rules are respected. In adolescents, the acquirement of a normal peak bone mass has to be guaranteed by the use of the OC. The dosage of the OC has to be adapted individually to the basic hormonal situation. In women over 40, contraindications such as hypertension, obesity, smoking or dyslipidemia have to be actively excluded. In both groups of age, the risk of a correctly indicated OC is inferior to the risk of an unwanted pregnancy.

[Contraception in women with special problems]. / Kontrazeption bei Problemfällen.

Thromboembolic, cardiovascular and cerebrovascular events are age-dependent. They are extremely rare in young women. In contrast to the progestogen-only pills, oral contraceptives (OC) increase the risk of venous thrombosis. However, decisive ist the genetic predisposition. In healthy non-smokers of less than 35 years of age, the risk to suffer from a myocardial infarction or a cerebrovascular accident is not increased by OC. Risk factors play a major role in the etiology of cardiovascular diseases. A detailed personal and family history is therefore mandatory before OC are prescribed. Very rarely, blood pressure is increased by OC. Although the incidence of such an increase is very low, blood pressure has to be measured regularly in pill users. Inspite of a current opinion, weight increase is rare in OC users. It depends mainly on the individual predisposition. An increased water retention can be reduced by a combined OC containing a progestagen with an antimineralocorticoid activity. Changes in insulin and blood sugar induced by low-dose OC are minimal so that they have no clinical relevance. OC do not increase the incidence of diabetes. Adrenal and thyroid function are not influenced by OC, there is no increased incidence of prolactinomas. Asthma is no contraindication against OC. If there is a cycle-dependent aggravation of the disease, OC might be beneficial. OC have no side-effects on the eye or the ear. In women suffering from lupus erythematodes having no renal participation, no increased antiphospholipid-antibodies and showing a stable or inactive disease, low-dose OC might be used.

[Does hormonal contraception increase the risk for tumors?]. / Erhöht die hormonale Kontrazeption das Tumorrisiko?

A non-contraceptive benefit of oral hormonal contraceptives (OC) is a diminished risk for certain benign as well as malignant tumours, such as benign breast tumours, uterine fibroids and ovarian cysts. Endometriosis itself is not positively influenced by OC, but dysmenorrhea is decreased. Modern low-dose OC do not increase the risk of liver cell adenomata or carcinomata. OC do not influence melanoma. Modern data do not suggest an increased risk for breast carcinoma in OC users. Long-term use of OC leads to a decreased risk of endometrial and colorectal carcinomata. Cervical carcinoma is not influenced directly by OC, but probably indirectly through a change in sexual behaviour. There is no increase of vulvar or vaginal carcinoma, even after long-term use of OC.

Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy.

In a large population-based case-control study in Germany, including 3,464 breast cancer cases aged 50-74 at diagnosis and 6,657 population based and frequency matched controls, we investigated the effects of menopausal hormone therapy (HT) by type, regimen, timing and progestagenic constituent on postmenopausal breast cancer risk overall and according to histological type. Data were collected by face-to-face interviews. Logistic and polytomous logistic regression analysis were used to estimate odds ratios (OR) and 95%-confidence intervals (95% CI). Risk of invasive breast cancer was significantly elevated in current users (OR, 1.73, 95% CI, 1.55-1.94) and heterogeneous by histological type (p < 0.01), being more than 2-fold higher for lobular and tubular than for ductal cancer. Risks for current users varied significantly by type and regimen of HT, with ORs per year of use of 1.05 (95% CI, 1.04-1.06) for continuous combined estrogen-progestagen, 1.03 (95% CI, 1.02-1.04) for cyclical EP and 1.01 (95% CI, 1.00-1.03) for estrogen-only therapy. No statistically significant increase in risk was observed after 5 years of cessation of HT use for any histological type. Analyses of progestagenic content by regimen revealed a significantly higher risk for continuously administered norethisterone- or levonorgestrel-derived progestagens than for continuously administered progesterone-derived progestagens (OR, 2.27, 95% CI, 1.98-2.62 vs. 1.47, 95% CI, 1.12-1.93, respectively, p = 0.003), which may be explained by dose rather than type of progestagen. These data suggest that the risks associated with menopausal HT differ by type and regimen of HT and histological type of breast cancer and may vary by progestagenic component, depending on the effective dose.

Test-retest reliability of self-reported reproductive and lifestyle data in the context of a German case-control study on breast cancer and postmenopausal hormone therapy.

PURPOSE: Studies using survey questionnaires to collect epidemiologic data rely on the accuracy of participants' self-reporting. As part of the quality control protocol for a large population-based case-control study of the association between postmenopausal hormone therapy (HT) and breast cancer in German women (the Mammakarzinom-Risikofaktoren-Erhebung [MARIE] study), the authors used test-retest to evaluate the reliability of women's self-reporting of a number of putative breast cancer risk factors, including HT, reproductive history, family history, and lifestyle. METHODS: Of those women interviewed between November 2002 and July 2003, 62 cases and 61 controls were re-interviewed an average of 10 months later, using a shortened version of the original study questionnaire. RESULTS: Agreement between the first and second interviews was assessed using Cohen's kappa and proportion of agreement. There was very good overall agreement between the two questionnaires for HT ever/never use (kappa = 0.90), type of therapy (kappa = 0.83), and form of application (kappa = 0.73) and good agreement for duration of use (kappa = 0.60). Agreement for other factors ranged from kappa = 1.00 for age at first birth to kappa = 0.43 for weekend bicycle riding. Agreement was nondifferential by disease status. CONCLUSIONS: These findings indicate that the MARIE survey instrument was of good quality and had a low likelihood of misclassification.

The selective estrogen receptor-beta agonist biochanin A shows vasculoprotective effects without uterotrophic activity.

OBJECTIVE: Current hormone therapy in postmenopausal women is associated with uterotrophic activity and cancer-promoting effects. In this experimental study, we compared the effects of the selective estrogen-receptor (ER) beta agonist biochanin A, and the selective ERalpha agonist ethinylestradiol, on the development of intimal hyperplasia after balloon injury and on uterus morphology. DESIGN: Female F344 rats with or without prior ovariectomy were used for aortic denudations. Animals remained untreated or received oral biochanin A (100 mg/kg) or ethinylestradiol (100 microg/kg). After 14 days, aortas and uteri were harvested for histologic and immunohistochemical analyses. Computerized assessments of aortic adhesion molecule expression, and isometric relaxation experiments, and uteri were analyzed. In vitro studies with smooth muscle cells and endothelial cells were performed to further investigate the effects of hormone treatment on cell proliferation, migration and adhesion molecule expression. RESULTS: Among untreated rats, ovariectomized animals tended to show greater neointimal hyperplasia and increased expression of the adhesion molecules 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Biochanin A treatment reduced neointima formation, inhibited VCAM-1 up-regulation, and improved the vascular relaxation response. No effect was observed on uterus growth or histology. Ethinylestradiol also reduced aortic neointima formation and inhibited VCAM-1 up-regulation, but failed to improve endothelial function and significantly induced uterus growth. Both agents showed antiproliferative and weak antimigratory effects on smooth muscle cells, and reduced VCAM-1 expression on stimulated endothelial cells in vitro. CONCLUSIONS: The ERbeta agonist biochanin A shows vasculoprotective effects without uterotrophic activity. Because hormone therapy may have cancer-promoting side effects, administration of ERbeta-selective agents might be alternatively used to reduce the risk of cardiovascular disease in postmenopausal women.

The phytoestrogen biochaninA weakens acute cardiac allograft rejection without affecting the reproductive system.

BACKGROUND: Since the two estrogen receptor isoforms ERalpha and ERbeta have been discovered it is unclear by which receptor immunomodulating or feminizing effects are mediated. In this study, the effects of the two selective ERalpha- and ERbeta-agonists ethinylestradiol and biochaninA, respectively, on acute cardiac allograft rejection, uterus growth, vascular adhesion molecule and MHC-II expression were investigated and verified using in vitro cell culture. METHODS: Heterotopic Lewis to ovarectomized F344 cardiac transplantations were performed. The study groups received supplemental biochaninA or ethinylestradiol, the control group received no treatment. Grafts and uteri were harvested on the fifth postoperative day and blood was taken for hormone plasma level quantifications. Purified Lewis aortic endothelial cell cultures were pre-treated with biochaninA or ethinylestradiol and stimulated with TNF-alpha or IFN-gamma for quantification of ICAM-1/VCAM-1 and MHC-II expression. Endothelium-lymphocyte adhesion assays were performed using purified F344 lymphocytes. RESULTS: Both biochaninA and ethinylestradiol treatment significantly reduced graft mononuclear infiltration of CD8(+) and ED1(+) cells and markedly reduced ISHLT grading compared to untreated controls. Either agent significantly inhibited lymphocyte adhesion, endothelial VCAM-1 upregulation during graft rejection and during TNF-alpha-stimulation in vitro, whereas no effect was observed for ICAM-1 upregulation. BiochaninA but not ethinylestradiol significantly reduced endothelial MHC-II upregulation in vivo and in vitro. Only ethinylestradiol treatment strongly affected uterus growth in ovarectomized recipients. CONCLUSIONS: Only the treatment with the phytoestrogen biochaninA reduced endothelial MHC-II expression in vivo and in vitro and weakened allograft rejection without affecting the reproductive system. Supplemental phytoestrogens may therefore provide further benefits in the clinical setting.

Laparoscopic oophoropexy for the treatment of recurrent torsion of the adnexa in pregnancy: case report and review.

OBJECTIVE: To introduce a new surgical approach, oophoropexy to prevent recurrent adnexal torsion. DESIGN: Case report and review of the literature. SETTING: The obstetrics and gynecology department of a university hospital. PATIENT(S): A 29-year-old pregnant patient who had three events of torsion of the adnexa after stimulation. INTERVENTION(S): Laparoscopic oophoropexy. MAIN OUTCOME MEASURE(S): Incidence of torsion. RESULT(S): No more torsion events were registered during the ongoing pregnancy. CONCLUSION(S): Laparoscopic oophoropexy is recommended in emergency situations to increase adnexal salvage and to prevent a recurrence.