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Menopausal hormone therapy (HT) is associated with an increased breast cancer risk among postmenopausal women. In this study, we investigated genetic effect modification of HT associated breast cancer risk in 3,149 postmenopausal breast cancer patients and 5,489 controls from the two German population-based case-control studies MARIE and GENICA. Twenty-eight polymorphisms of 14 candidate genes including two drug and hormone transporter genes (ABCB1/MDR1 and SHBG), four genes involved in cell cycle regulation (BRCA1, P21/CDKN1A, STK15/AURKA and TP53), six cytokine genes (IGFBP3, IL6, TGFB1, TNF, LTA and IGF1), and two cytokine receptor genes (EGFR and ERBB2) were genotyped using validated methods. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen-progestagen therapy and estrogen monotherapy use with regard to breast cancer risk assuming log-additive and co-dominant modes of inheritance. Women homozygous for the major ABCB1_rs2214102_G allele were found to be at a significantly increased breast cancer risk associated with combined estrogen-progestagen therapy [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.12-1.23, P (interaction) = 0.022]. Additionally, risk associated with estrogen monotherapy was modified by BRCA1_rs799917. We observed a trend with increasing minor T alleles leading to the highest risk in homozygous carriers of the minor allele [OR (95% CI) = 1.17 (0.98-1.39), 1.06 (0.98-1.14), and 1.02 (0.94-1.11) for homozygous minor, heterozygous, and homozygous major allele carriers, respectively; P (interaction) = 0.032]. Our results suggest that genetic variants in ABCB1 and BRCA1 may modify the effect of HT on postmenopausal breast cancer risk.

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 (Pheterogeneity = 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). (Cancer Epidemiol Biomarkers Prev 2009;18(8):2207–13)

Seitdem der Zusammenhang zwischen der Dosis des Ethinylestradiols (EE) und dem Risiko venöser thromboembolischer Erkrankungen erkannt wurde, war die Entwicklung der Ovulationshemmer (OH) durch eine kontinuierliche Reduktion der EE-Dosis geprägt. Die damit verbundene Abnahme der Ovulationshemmwirkung der Estrogenkomponente wurde durch die Einführung potenter Gestagene kompensiert, sodass die kontrazeptive Sicherheit bei geringerem Nebenwirkungsprofil erhalten blieb. Auf Akne und Seborrhö haben auch ultra-niedrig dosierte OH einen günstigen Einfluss. Die Ergebnisse zu den Wirkungen der ultra-niedrig dosierten OH auf das Skelett sind widersprüchlich. Da es zwischen Estradiol und EE fundamentale Unterschiede gibt, sinkt das thromboembolische Risiko bei parenteraler Gabe von EE nicht ab und nimmt beim kontrazeptiven Pflaster sogar zu. EE wird nicht an SHBG gebunden. Aufgrund der Ethinylgruppe wird EE relativ langsam inaktiviert, sodass auch das in gleichmäßig niedrigen Konzentrationen in die Leber gelangende EE zahlreiche estrogenabhängige hepatische Parameter signifikant verändert. Dazu zählt auch die Hämostase und es ist anzunehmen, dass entsprechende Veränderungen für das erhöhte Thromboserisiko beim kontrazeptiven Pflaster verantwortlich sind. Eine Verkürzung des hormonfreien Intervalls der Pille auf 5 oder 4 Tage führt zu einer völligen Suppression der Ovarialfunktion, einer zuverlässigen Hemmung der Ovulation und einer Verstärkung der kontrazeptiven Wirksamkeit, auch wenn die EE-Dosis auf 20 μg oder 15 μg reduziert wird.

Als nicht-kontrazeptiven Nutzen senken orale hormonale Kontazeptiva (OH) das Risiko von bestimmten benignen und malignen Tumoren. Dazu gehören benigne Brusttumoren, Uterusmyome und funktionelle Ovarialzysten. Eine Endometriose wird selbst durch OH nicht beeinflusst, doch kommt es zu einer Verminderung der Dysmenorrhoe. Bei nieder dosierten modernen OH scheint das Risiko für Leberzelladenome und -karzinome nicht erhöht zu sein. Melanome werden durch OH nicht beeinflusst. Hinsichtlich des Mammakarzinoms kann aus den derzeit bekannten Daten kein erhöhtes Risiko abgelesen werden. Auf das Endometriumkarzinom wirken OH langfristig protektiv, ebenso auf kolorektale Karzinome. Zervixkarzinome werden nicht direkt durch OH beeinflusst, jedoch wahrscheinlich durch ein unter OH anderes Sexualverhalten. Auch unter langjähriger OH-Einnahme fand sich keine erhöhte Inzidenz von Neoplasien der Vagina oder Vulva.

Die Nutzen-/Risiko-Bilanz einer hormonalen Kontrazeption (OH) ist sowohl bei Jugendlichen als auch bei der Frau über 40 Jahren günstig, sofern bestimmte Regeln beachtet werden. Bei Jugendlichen betrifft dies insbesondere den Ermöglichung des Erwerbs einer normalen Peak-Bone-Mass durch die Wahl eines korrekt dosierten OH, bei älteren Frauen den aktiven Ausschluss von Kontraindikationen wie arterielle Hypertonie, Adipositas, Rauchen und Dyslipidämie. In beiden Altersgruppen ist in jedem Falle das Risiko einer korrekt indizierten OH geringer als dasjenige einer unerwünschten Schwangerschaft.

Umfragen ergeben, dass die Mehrheit der Frauen eine Änderung ihres Zyklusverhaltens im Sinne von weniger Menstruationen oder eine Amenorrhoe wünschen. Dies gilt gleichermaßen für Frauen mit Spontanzyklen wie für OH-Anwenderinnen. Die Hauptgründe dafür sind weniger Menstruationsbeschwerden, bessere Hygiene, bessere Lebensqualität und weniger Blutverlust. Bei den Frauen, die regelmäßige monatliche Blutungen wünschen, steht vor allem die Ansicht im Vordergrund, dass die Unterdrückung der Menstruation etwas «Unnatürliches» sei. Es ist deshalb notwendig, die Frauen darüber zu informieren, dass die kontrazeptive Sicherheit unter dem Langzyklus-Schema noch gesteigert wird und eine Beeinträchtigung der Fertilität nicht zu erwarten ist. Der Vorteil des Langzyklus ist eine Reduktion der Zahl der Entzugsblutungen und die Vermeidung der durch das hormonfreie Intervall ausgelösten Hormonschwankungen mit ihren psychischen und somatischen Beschwerden sowie eine erhöhte kontrazeptive Sicherheit. Folgende zyklus- und menstruationsabhängige Beschwerden werden als Indikation für die Anwendung des Langzyklus genannt: Endometriose, Menorrhagien, Dysmenorrhöen, hämorrhagische Diathesen, Uterusmyome, Polyzystisches Ovarsyndrom, Estrogen-Entzugs-Migräne in der Pillenpause sowie Prämenstruelles Syndrom.

Thromboembolische, kardiovaskuläre und zerebrovaskuläre Ereignisse sind altersabhängig und bei gesunden junge Frauen äußerst selten. Im Gegensatz zu reinen Gestagen-Präparaten erhöhen Ovulationshemmer (OH) das Risiko venöser Thrombosen, wobei der genetischen Prädisposition die entscheidende Rolle zukommt. Bei gesunden Nichtraucherinnen unter 35 Jahren ist das Risiko für Herzinfarkt und Schlaganfälle nicht erhöht. Bei der Entstehung kardiovaskulärer Erkrankungen spielen Risikofaktoren eine wichtige Rolle. Eine sorgfältige Eigen- und Familienanamnese ist vor jeder Verschreibung eines OH Pflicht. Sehr selten kann der Blutdruck unter OH ansteigen. Auch wenn die Inzidenz niedrig ist, muss bei allen bei Frauen unter OH regelmäßig der Blutdruck kontrolliert werden. Gewichtszunahmen unter OH sind entgegen einer weit verbreiteten Meinung selten und von der individuellen Disposition abhängig. Eine vermehrte Wasserretention kann durch einen kombinierten OH mit antimineralokortikoider Zusatzwirkung gebessert werden. Die bei niedrigdosierten oralen Kontrazeptiva beobachteten Veränderungen von Insulin und Blutzucker sind so gering, dass sie keine klinische Bedeutung besitzen. Durch OH wird die Inzidenz von Diabetes mellitus nicht erhöht. Nebennierenrinde- und Schilddrüsenfunktion werden durch OH nicht beeinflusst, es findet sich auch keine erhöhte Inzidenz von Prolaktinomen. OH sind bei Asthmatikerinnen nicht kontraindiziert. Bei zyklusabhängiger Verschlechterung des Krankheitsbildes kann sogar mit einer Besserung gerechnet werden. Augen und Gehör werden durch OH nicht verschlechtert. Bei Patientinnen mit Lupus erythematodes ohne Nierenbeteiligung, ohne hohe Antiphospholipid-Antikörper und mit einer stabilen oder inaktiven Erkrankung ist die Gabe von niedrig-dosierten OH vertretbar.

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.

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.

Background Since the two estrogen receptor isoforms ERα and ERβ have been discovered it is unclear by which receptor immunomodulating or feminizing effects are mediated. In this study, the effects of the two selective ERα- and ERβ-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-α or IFN-γ 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-α-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.

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.

Leider besteht für diesen Artikel keine Zusammenfassung. Als Einstieg stellen wir den Textanfang zur Verfügung. Seit einiger Zeit wird ein Gentest angeboten, mit dem sich angeblich das individuelle Risiko für z.B. Herz-/Kreislauferkrankungen, Thrombosen, Osteoporose, Mammakarzinom oder Schwangerschaftskomplikationen durch die Analyse von 18 genetischen Parametern bzw. deren Polymorphismen erkennen lässt. Anhand der Ergebnisse dieses Tests soll es dann möglich sein, für jede Frau die optimale Hormonsubstitution festzulegen und die individuellen Krankheitsrisiken durch geeignete Massnahmen zu minimieren. Nach der Veröffentlichung einer kurzen Stellungnahme zu diesem Gentest im Addendum der jüngsten Empfehlungen des Zürcher Gesprächskreises zur Hormonsubstitution in ‘Frauenarzt’ 2/2002 gingen verschiedene Kommentare ein. Der Zürcher Gesprächskreis sieht sich deshalb veranlasst, zum Thema Polymorphismen eine ausführliche Stellungnahme abzugeben.

Kosten und Bedarf an Know-how bei der Gestaltung und Betreibung von Websites für Arztpraxen und Kliniken können zu einer Zusammenarbeit mit industriellen Anbietern führen. Daraus können sich finanzielle Verflechtungen ergeben, für die Regelungsbedarf besteht. Von Werbung wird abgeraten, diese neu aber nicht mehr grundsätzlich verboten; Links auf fremden Websites sind zur alleinigen Adressenvermittlung zulässig; Annahme von Drittmitteln im Zusammenhang mit der Homepage ist offenzulegen; medizinische Information muss von Fachpersonen stammen. Für Praxen und Kliniken wird zur Einrichtung und Betreibung von Websites die Übernahme des HONcode und der Verzicht auf den Aufbau einer zusätzlichen standeseigenen Zertifizierung empfohlen.

The counseling of patients who want to take oral contraceptives (OCs) is necessary because of contraindications risk factors and drug cross reactions. Important elements in the anamnesis should be considered: familial history of circulatory diseases diabetes mellitus coagulation disorders smoking and high blood pressure. Contraindications include: liver diseases disorders of bile secretion intrahepatic cholestasis liver tumors thromboembolic diseases circulatory diseases breast cancer high blood pressure and severe hypertriglyceridemia. 4-6 weeks prior to scheduled operation which poses the risk of increased thromboembolism OCs should be discontinued. There is no convincing evidence about the increase of breast cancer through the use of OCs. It is unclear whether the increased rate of dysplasia of the uterine cervix is induced by contraceptive steroids or other accompanying factors particularly viral infections. Women over 40 years of age can continue using low-dose OCs provided the risk factors are not present. The risk of endometrial and ovarian cancer is reduced with long-term use of OCs. In addition OCs have a beneficial effect on the incidence of various diseases e.g. benign breast ailments ovarian cysts bleeding disorders dysmenorrhea and acne. The Zurich Discussion Group supports the formulation proposed by the Committee of Hormonal Toxicology of the German Society for Endocrinology to wit it is not clear whether hormonal contraceptives can promote the occurrence or growth of breast cancer. On the basis of the results of available investigations OCs do not increase the risk of breast cancer. Early menarche late menopause anovulatory cycles and nulliparity may suggest the influence of ovarian factors in the etiology of breast cancer. The results of numerous in vitro investigations have suggested that synthetic estrogens influence the growth of normal or malignant breast gland cells in a way different from natural estrogens. The results of more than 50 retrospective case control studies revealed no increased risk of breast cancer in OC users.

Menopausal hormone therapy (HT) is associated with increased breast cancer risk among postmenopausal women. Nuclear receptors are involved in steroid hormone- and xenobiotic-mediated signal transduction playing a crucial role in regulating gene expression. Therefore, variations within these genes may influence HT-associated breast cancer risk. We investigated 3,149 postmenopausal breast cancer patients and 5,489 controls from 2 German population-based case-control studies. Thirty-three polymorphisms selected on the basis of known or putative functional relevance located in ESR1, ESR2, PGR, PXR and AR were genotyped. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen-progestagen therapy and of estrogen monotherapy with regard to breast cancer risk assuming log-additive and codominant modes of inheritance. We observed an increased risk for women carrying short AR_(CAG) alleles of22 repeats associated with combined estrogen-progestagen therapy compared with those with long alleles (or =22 repeats) (p(interaction) = 0.03). Additionally, risk associated with combination therapy use was significantly modified by 2 PXR polymorphisms with reduction of risk effects in carriers of the minor PXR_rs6785049_G and PXR_rs1054191_A alleles (p(interaction) = 0.04 and 0.05, respectively). Variants in both ESR1 and ESR2 modified risk associated with estrogen monotherapy use. Higher risk were observed in homozygotes for the major ESR1_rs910416_T allele (p(interaction)0.01) and in homozygotes for the minor ESR2_rs1271572_T, major ESR2_rs4986938_G and minor ESR2_rs928554_G alleles (p(interaction) = 0.02, 0.05, 0.02, respectively). Risk effect modification by ESR1_rs910416 and AR_(CAG)n polymorphisms remained significant after correction for multiple testing. We conclude that genetic variants in nuclear receptor genes may modify HT-associated postmenopausal breast cancer risk.

Long-term hormone therapy (HT) is a recognized risk factor for postmenopausal breast cancer. Elevated steroid hormone levels play a critical role in breast carcinogenesis and this may be contributed by the efficiency of hormone biosynthesis. Within this context, genetic polymorphisms related to steroid hormone biosynthesis may modify HT-associated postmenopausal breast cancer risk. CYP17 is a key player of this pathway and the CYP17A1_-34_TC polymorphism has been suggested to affect breast cancer risk in women using long-term HT. We genotyped 13 polymorphisms of seven genes of the steroid hormone biosynthesis pathway in 3,149 postmenopausal breast cancer patients and 5,489 age-matched controls from Germany. We observed a significant interaction of CYP17A1_-34_TC and HT use on breast cancer risk in a co-dominant model (P (interaction) = 0.007). Current users of estrogen monotherapy showed a significantly increased risk for duration of use per 5-year increment when they were carriers of the CYP17A1_-34_TC genotype (OR 1.13, 95% CI: 1.04-1.23 per 5 years of use). We conclude that CYP17A1_-34_TC may be part of the genetic background to contribute to postmenopausal breast cancer risk in women using estrogen monotherapy.

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. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1188–96)

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.

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.

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.

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.

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.

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 (p0.01), 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.

Ovarian stimulation cycles were initiated using human menopausal gonadotropin (HMG) in 318 women (643 cycles) without pretreatment and in 341 women (525 cycles) after pituitary desensitization by pretreating with the gonadotropin-releasing hormone agonists (GnRH-A) buserelin acetate or triptorelin acetate. Significantly higher pregnancy rates were observed in the GnRH-A/HMG group (15%) as compared to the HMG group (7%) following in vitro (p less than 0.05) but not in vivo fertilization therapy (14 vs. 9%, respectively). After in vitro fertilization, the rates increased with increasing length of the active phase of follicular maturation. Gamete intrafallopian transfer, performed only in the GnRH-A/HMG group, led to a pregnancy rate of 34%. Overall, there was a clear trend to higher pregnancy rates in the GnRH-A/HMG group (16%) as compared to the HMG group (8%). Abortion rates were comparable in both groups (24 vs. 19%). The higher pregnancy rates in the GnRH-A/HMG group were attributable to enhanced follicular maturation and optimized ovarian stimulation produced by the hypogonadotropic state. However, an increased risk of the ovarian hyperstimulation syndrome was observed in these patients.

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 κ and proportion of agreement. There was very good overall agreement between the two questionnaires for HT ever/never use (κ = 0.90), type of therapy (κ = 0.83), and form of application (κ = 0.73) and good agreement for duration of use (κ = 0.60). Agreement for other factors ranged from κ = 1.00 for age at first birth to κ = 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 Million Women Study [1] is in the number of participants until now the largest observational study on the relationship between hormone treatment in the postmenopause and breast cancer. There is, however, only a very short observation time of 2.6 years for incident cases and 4.1 years for fatal cases. The elevated risk of breast cancer among women who are recent hormone users is in agreement with the results of other recent or older studies as well as the more elevated risk in combined treatment with estrogens and progestins compared with estrogen treatment alone. Surprising, however, is the risk elevation already within the first year of combined treatment. This is in disparity to other studies which found an increased risk only after longer treatment, it is also biologically not plausible or could be explained only by a promotion of pre-existing cancers. Even more surprising is that the risk could not be seen anymore already 1 year after stopping treatment. The relative risk was in the prospective randomised WHI-Study [2] in the continuous combined HRT-Group significantly increased (RR /1.24) during observation time of 5.6 years. During estrogen only treatment however, an equivalent increase was not observed until now. In the Million women study the relative risk in the estrogen /progestin group was 2.0 and in the estrogen only group 1.3. It is remarkable that also during treatment with tibolone the risk was elevated 45%. The increased mortality in the Million women study, which, however, is not significant (P /0.05) is in disagreement with the most previous studies. In a review regarding ten studies, a significantly reduced mortality was found in two studies, in five a decreased mortality which was not significant and only in three studies an increased mortality, which, however, was also not significant [3]. In the large prospective Cohort Study of the American Cancer Society (regarding 422 000 postmenopausal women), among the registered 1469 fatal cases a significantly decreased mortality was found of 16% among the hormone users [4]. Which influence has this study on our prescription attitudes? We will discuss the data of this study in comparison to the data of previous studies. Our recommendations since years have been that hormone treatment in the post menopause has to be based on an indication. But there is not another treatment possibility as effective for the estrogen deprived climacteric complaints than the treatment with estrogens or estrogens and progestins and on this indication the risk benefit analysis must be based and our patients have to be informed on both. * Tel.: /49-40-42803-3540; fax: /49-40-42803-2523. E-mail address: braendle@uke.uni-hamburg.de (W. Braendle). Maturitas 46 (2003) 101 /102