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Dienogest (DNG) has the essential properties of an effective progestogen for use in a new contraceptive pill using estradiol valerate as estrogenic component -- it inhibits ovulation and protects against endometrial proliferation. DNG is a derivative of norethisterone (NET), but has a cyanomethyl- instead of an ethinyl-group in C17 position which may offer a variety of benefits regarding hepatic effects. The similarity to NET is reflected in the high endometriotropy and in similar pharmacokinetics like short plasma half-live and high bioavailability. However, DNG also elicits properties of progesterone derivatives like neutrality in metabolic and cardiovascular system and considerable antiandrogenic activity, the latter increased by lack of binding to SHBG as specific property of DNG. It has no glucocorticoid and antimineralocorticoid activity and has no antiestrogenic activity with the consequence that possible beneficial estradiol effects should not be antagonized. This may be of special importance for the tolerability and safety of the first pill with estradiol valerate instead of ethinylestradiol, although well-designed postmarketing studies are still ongoing to demonstrate what can be expected on the basis of pharmacology.

Dienogest (DNG) is already used in hormone therapy, since recently being also the progestogenic component of the first estradiol based contraceptive pill. Data on breast cancer risk are currently not available. Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in tissues of breast cancer patients and has already been proposed as a predictor for breast cancer risk.MCF-7 cells overexpressing PGRMC1 were stimulated with DNG, medroxyprogesterone acetate (MPA), norethisterone (NET) and progesterone (P) as well as sequentially and continuously combined with estradiol (E2).DNG and MPA alone elicited a significant proliferation at 10⁻⁶ and 10⁻⁵ M. NET increased cell proliferation at all concentrations tested whereas P showed no effect. E2 alone elicited a significant increase at 10⁻¹⁰ M, no effect was seen at 10⁻¹² M. Addition of the progestins (10⁻⁶ M) to E2 at 10⁻¹⁰ M had, compared to E2 only, no additional proliferating effect. However, at the low E2 concentration, DNG, MPA and NET significantly increased the E2-stimulated cell proliferation.DNG increased proliferation alone and in combination with low E2 concentrations. Thus a progestogen-derived breast cancer risk in the presence of low E2 concentrations cannot be excluded at least in women overexpressing PGRMC1.

This randomized double-blind study was conducted to investigate the effects of 17 beta-estradiol plus norethisterone acetate, and raloxifene, on nitric oxide (NO), prostacyclin (PGI2) and endothelin-1 (ET-1) serum levels in postmenopausal women. Treatment was initiated after a 28-50 day placebo period. Fourteen women were treated daily with 17 beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2 + NETA), and 14 with raloxifene HCl 60 mg for a period of 6 months. Serum NO, PGI2 and ET-1 levels were estimated at baseline, after placebo, and at months 3 and 6. E2 + NETA decreased NO levels significantly, while raloxifene did not cause any appreciable change. Both regimens decreased PGI2 levels and ET-1 levels significantly. Finally, E2 + NETA and raloxifene increased the NO/ET-1 ratio by 61.4% and 81.1%, respectively. In conclusion, both regimens may exert a cardio-protective effect by decreasing ET-1 levels and increasing the NO/ET-1 ratio. In contrast, both regimens had a negative influence on PGI2 levels.

Trimegestone is a novel norpregnane progestin, which is being developed, in combination with 17 beta-estradiol, for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. A model of osteoporosis in the ovariectomized rat has been used to evaluate the effects of 17 beta-estradiol and trimegestone, alone and in combination, on bone and uterus in these animals. Two treatment protocols were investigated, preventive with treatment starting immediately after ovariectomy and curative with treatment starting 1 or 6 months after ovariectomy. 17 beta-Estradiol was administered subcutaneously at a dose of 10 micrograms/kg/day with trimegestone or norethisterone being administered orally at a dose of 1 mg/kg/day; treatment was given 5 days per week. Treatment on both protocols was for 6 months. Given alone, 17 beta-estradiol maintained bone mass, either partially or completely, when given on the preventive protocol, or on the curative protocol with treatment starting 1 month after ovariectomy; it did not restore bone mass when given on the curative protocol with 6 months lapsing between ovariectomy and start of treatment. Trimegestone did not block the beneficial effects of 17 beta-estradiol on bone. 17 beta-Estradiol induced uterine hypertrophy on all these protocols and this was blocked completely by trimegestone. Trimegestone administered alone had no effect on bone or uterus but, when given in combination with 17 beta-estradiol, it did not inhibit the effect of 17 beta-estradiol in maintaining bone mass but completely blocked its uterotropic effect. Norethisterone at a similar dose did not inhibit the effects of 17 beta-estradiol on bone but also did not block its uterotropic effect.

The study aimed to determine if the addition of daily low-dose oral estrogen with a cyclical progestogen given to young women using a depot gonadotropin-releasing hormone (GnRH) analog implant for the treatment of their premenstrual syndrome (PMS) would affect the clinical outcome. In a double-blind placebo-controlled study in a specialist premenstrual syndrome clinic setting, 60 women aged between 20 and 45 years were randomized to one of three treatment groups: Group A (placebo implant four weekly + placebo tablets daily), Group B (goserelin 3.6 mg implant four weekly + estradiol valerate 2 mg daily with norethisterone 5 mg from days 21-28 of a 28-day cycle) or Group C (goserelin 3.6 mg implant four weekly + placebo tablets daily). Differences between PMS scores at 2, 4 and 6 months were compared with pretreatment values. There was a significant improvement in PMS scores in Group C (Zoladex + placebo) after 2, 4 and 6 months of treatment when compared to pretreatment values and Group A (placebo + placebo). The addition of a low-dose oral estrogen with a cyclical progestogen to GnRH analog treatment (Group B) resulted in a less dramatic response when compared to pretreatment values and no significant improvement when compared to Group A (placebo + placebo) at 2, 4 and 6 months of treatment. The addition of a low-dose oral estrogen with a cyclical progestogen to depot GnRH analog therapy in the treatment of PMS reduces the clinical response.

Objectives: A review of the metabolic effects of oral contraceptives (OCs) in women with insulin-dependent diabetes mellitus (IDDM) and previous gestational diabetes mellitus (GDM).Methods: The effects on glycometabolic control and lipid metabolism were studied in women with well controlled IDDM using low-dose OCs containing ethinyl estradiol combined with norethisterone, levonorgestrel or gestodenc. The hemostatic and endothelial function was also studied in the diabetic women using the gestodene-containing preparation. In women with previous GDM, investigations on insulin sensitivity were performed during intake of a triphasic lowdose oral contraceptive with levenorgestrel.Results: In women with IDDM the glycemic control was not changed by the OCs and none of the treatment regimens were associated with changes in plasma lipids linked to increased risk of atherogenesis. Analysis of the hemostatic balance during intake of the gestodene-containing preparations gave indication of increased fibrin formation ...