Disease relevance of Dienogest

• Androgenic symptoms (including hirsutism, seborrhoea, alopecia, acne vulgaris and hair and skin greasiness) improved in women treated with dienogest plus ethinylestradiol [1].
• A noncomparative multicentre study in 1501 postmenopausal women demonstrated that adverse events associated with estradiol valerate 2mg/dienogest 2mg once daily for 48 weeks included breakthrough bleeding, mastalgia, headache, abdominal pain, hypertension, thrush, migraine, weight gain, increase in endometrial thickness and metrorrhagia [2].
• The present study was conducted to confirm the effects of dienogest on experimental endometriosis in rats and to elucidate its mechanism of action [3].
• Microbial transformation of 17 alpha-cyanomethyl-17-hydroxy-4,9-estradien-3-one (STS 557) and 17 alpha-cyanomethyl-19-nortestosterone by Mycobacterium smegmatis [4].
• While in the urinary metabolite pattern more polar metabolites dominated, in bile of animals with a bile fistula, a dienogest metabolite of medium polarity was prevalent [5].

High impact information on Dienogest

• Estradiol valerate 2mg/dienogest 2mg is an oral estrogen/ progestogen formulation that has been approved throughout the European Union for the treatment of climacteric symptoms in postmenopausal women [2].
• Dienogest inhibits ovulation, produces secretory transformation of the endometrium and has antiproliferative effects [1].
• The progestogen dienogest exhibits highly selective binding to the progesterone receptor [1].
• Formulations containing the newer progestogens are, however, preferable in patients with hyperandrogenaemia, the symptoms of which may be improved by the suppression of total and free testosterone and an increase in SHBG; an additional beneficial effect of the antiandrogenic properties of dienogest or nomegestrol remains to be proven [6].
• DNA fragmentation, DNA repair and apoptosis induced in primary rat hepatocytes by dienogest, dydrogesterone and 1,4,6-androstatriene-17beta-ol-3-one acetate [7].

Chemical compound and disease context of Dienogest

• These findings suggest that dienogest is not a pure progestin and appears to induce fewer side effects than drugs currently on the market for the treatment of endometriosis [8].
• In comparison with MPA and danazol, dienogest may induce a relatively high incidence of bleeding in patients with endometriosis partially because of its minimal effect on hemostasis [9].
• Intramuscular administration of STS 557 (17 alpha C-cyanomethyl-17 beta-hydroxy-estra-4,9(10)-diene-3-one) at a daily dose of 12 mg/monkey for 8 weeks induced severe oligospermia to complete azoospermia by the 9th week of initiation of treatment with concomitant decrease in the serum level of testosterone [10].
• At a dose of 5 mg STS 557 per day, male sterility was associated with reduction of sperm motility and semen fructose content [11].
• Toxicity of the progestagen STS 557 compared to levonorgestrel in beagles after oral administration for 6 months [12].

Biological context of Dienogest

• The biotransformation of the progestagen dienogest (17 alpha-cyanomethyl-17 beta-hydroxy-4,9-estradien-3-one) was studied in vivo in female rabbits and in vitro by liver homogenates from female rabbits and rats [5].
• Studies on the hydrogenation of the progestagen dienogest in vivo and in vitro in the female rabbit [5].
• In contrast to the rapid enzymatic hydrolysis of nonsteroidal nitriles, the nitrile group of dienogest was cleaved very slowly [13].
• Effect of dienogest-containing oral contraceptives on lipid metabolism [14].
• Dienogest caused no change in the bleeding time at a single dose of 100 mg/kg or at a repeated dose of 10 mg/kg per day for 2 weeks [9].

Anatomical context of Dienogest

• In this study, we investigated the direct effects of dienogest in differentiation and proliferation of human endometrial stromal cells (ESC) in vitro [15].
• In vitro experiments showed that dienogest at concentrations up to 10 microM had little or no effect on the proliferation of plasminogen activator activity or formation of tube-like structures by microvascular endothelial cells [16].
• Oral administration of dienogest (1 mg kg(-1) day(-1)) for 5 consecutive days significantly suppressed angiogenesis induced by S-180 mouse tumor cells in the mouse dorsal air sac assay [16].
• Effect of STS 557 on semen composition, fertility and sexual behaviour of male rabbits [11].
• Growth-stimulating effect of dienogest, a synthetic steroid, on rodent, canine, and primate mammary glands [17].

Associations of Dienogest with other chemical compounds

• As shown by the thymidine uptake method, there was a dose-dependent inhibition of ESC proliferation with dienogest (P < 0.01, control versus concentrations >10(-7) mol/l) [15].
• The significant inhibition of ESC proliferation by dienogest (10(-7) mol/l) was partially reversed by RU-486 (10(-6) mol/l) [15].
• The progestogenic component of the pill may elicit an impact on this oestrogen-induced vasodilation, which, however, seems to be minimized in the case of the new compound dienogest, a C-19 progestin with antiandrogenic properties [18].
• The results of the present investigation indicate that the modulatory effects on ovarian function of the monophasic oral-contraceptive containing 30 micrograms ethinyl estradiol combined with 2.00 mg dienogest lead to adequate suppression of ovarian activity and effective inhibition of ovulation [19].
• In conclusion, the DNG-containing OCs caused a higher rise in SHBG and TBG levels than the LNG-containing preparation [20].

Gene context of Dienogest

• Lack of stimulatory effect of dienogest on the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by endothelial cell as compared with other synthetic progestins [21].
• Addition of progesterone (10(-10)-10(-7) M) or dienogest (DNG) (10(-10)-10(-8) M) did not affect IL-1beta-stimulated ICAM-1 or VCAM-1 expression [21].
• In users of the DNG-containing OCs, the reduction in total and free protein S, and in t-PA and PAI was dependent on the EE dose, while factor VII activity was elevated, but not significantly different from EE/LNG [22].
• Except for EE/EV/DNG, which increased prolactin significantly during the third and sixth cycles, no change was observed with the EE-containing preparations [20].
• Protein C activity increased during the treatment with 30 micrograms ethinyl estradiol and 2.00 mg dienogest, and was higher than that of the placebo group in which this parameter decreased during the treatment cycle [23].

Analytical, diagnostic and therapeutic context of Dienogest

• Urinary metabolites of the new progestagen STS 557 (17 alpha-cyanomethyl-17-hydroxy-4,9-estradien-3-one) were isolated and characterized following oral administration of the 14 alpha, 15 alpha-tritium labelled compound to dogs and rats [24].
• In a prospective, double-blind, randomized study postmenopausal women were given continuous combined hormone replacement therapy (HRT) either as estradiol valerate 2 mg/dienogest 2 mg, (E2V/DNG) or estradiol 2 mg/noretisterone acetate 1 mg (E2/NETA) for 6 months [25].
• Orally administered dienogest (17alpha-cyanomethyl-17beta-hydroxy-estra-4,9-diene-3-one) is efficacious against human hormone-dependent cancer xenografts in severely immunodeficient mice and in rats with experimental endometriosis, but its mechanisms of action remain unclear [16].
• Dienogest is as effective as triptorelin in the treatment of endometriosis after laparoscopic surgery: results of a prospective, multicenter, randomized study [26].
• The ratio after ethinyl estradiol and dienogest was significantly lower after treatment [27].

References