Clinical findings with the oral contraceptive combination ethinylestradiol/dienogest in the Czech Republic.

The efficacy and safety of the low dose monophasic oral contraceptive (OC) combination containing 30 micrograms of ethinylestradiol (EE) and 2.0 mg of dienogest (DNG) (EE/DNG) was evaluated in a prospective, open-label, multicenter, uncontrolled, phase III trial. The trial was carried out in six hospitals by 36 investigators in the Czech Republic, and included 557 healthy women (aged 18-35 years), over 12 cycles, with a total of 6051 cycles. EE/DNG provided a reliable ovulation inhibition. The contraceptive efficacy study showed an adjusted Pearl index of 0.198 on the basis of three pregnancies occurring during 6051 cycles. EE/DNG provided good cycle control, reduced the incidence of intermenstrual bleedings, the intensity of menstrual bleeding and frequency of dysmenorrhea. Due to the antiandrogenic properties of the progestogen component DNG, EE/DNG improved androgen-related conditions, such as skin blemishes, hair greasiness and acne vulgaris. From 108 women with acne, 62 (57%) improved after the 6th cycle, and 16 (15%) were healed. Similar changes were found after cycle 12. Breast tenderness and headache were the most frequent of the common complaints due to treatment with EE/DNG. The frequency of all complaints decreased steadily over time. Only 7.7% of subjects discontinued due to adverse reactions. No thrombophlebitic events were noticed.

Correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in vascular endothelium with toxicity in early life stages of lake trout.

Edema and cardiovascular dysfunction occur in vertebrates exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early development. This study examined cytochrome P4501A (CYP1A) induction in endothelium and its possible association with mortality due to the edema and vascular effects of TCDD in lake trout early life stages. Lake trout (Salvelinus namaycush) eggs were injected at 24-50 hr postfertilization with 0.2 microl of 50 mM phosphatidylcholine liposomes or liposomes containing TCDD to give seven doses ranging from 11 to 176 pg TCDD/g egg. Doses of TCDD greater than 44 pg/g egg elicited hemorrhages; yolk sac, pericardial, and meningial edema; craniofacial malformations; regional ischemia; growth retardation; and mortality at the sac fry stage of development. Expression of CYP1A was assessed at four developmental stages, by immunohistochemical analysis of serial sections of individual fish with monoclonal antibody 1-12-3 to teleost CYP1A. CYP1A staining occurred in endothelial cells of many organs of TCDD-exposed but not vehicle-exposed embryos at 1 week prehatch and sac fry at 2 weeks posthatch. Earlier developmental stages examined were negative for CYP1A expression at any dose of TCDD. The strongest response occurred in sac fry at TCDD doses greater than 88 pg TCDD/g egg but was detected at doses as low as 22 pg TCDD/g egg. CYP1A staining in endothelium appeared at lower doses and was stronger than that in other cell types, in both prehatch embryos and posthatch sac fry. Thus, the vascular system is a major initial site affected by TCDD in lake trout early life stages, and the vascular endothelium is a cell type uniquely sensitive to induction of CYP1A in these developing animals. Based on an index of immunohistochemical staining of CYP1A, endothelial CYP1A induction in sac fry by TCDD occurred with an ED50 of 64-69 pg TCDD/g egg, similar to the dose-response for mortality occurring during the sac fry stage of development (LD50 = 47 pg TCDD/g egg). The correlations seen here suggest that CYP1A or aryl hydrocarbon receptor (AhR) in the endothelium may be linked to early lesions that result in TCDD-induced vascular derangements leading to yolk sac, pericardial, and meningial edema that is associated with lake trout sac fry mortality, but the precise mechanism remains to be determined.