Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression.

OBJECTIVE: This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien/Lafamme) over 24 weeks on postmenopausal depression. METHOD: A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD) > or =16 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final score < or =8 (corresponding to an improvement of > or =50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or sleep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND). RESULTS: The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p < 0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p < 0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35). CONCLUSION: The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome.

Breast cell proliferation in postmenopausal women during HRT evaluated through fine needle aspiration cytology.

The basis of breast cancer risk associated with hormonal therapies may lie in the regulation of cell proliferation. 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. Fine needle aspiration (FNA) biopsies were used for immunocytochemical analysis of breast cell proliferation before and during treatment. From 45 women completing the study 135 biopsies were obtained. In the total material there was a more than 4-fold increase in proliferation between baseline and 3 months (p < 0.001). The mean percentage of MIB-1 positive breast cells increased from 2.2 to 9.1%. In some individual women values were as high as 25%. No further increase was recorded at 6 months. While numerical values were somewhat lower in the E2V/DNG group, there were no significant differences between treatments. There was a positive correlation between breast cell proliferation (MIB-1%) and circulating levels of both estradiol (r(s) = 0.54, p < 0.01) and estrone (r(s) = 0.53, p < 0.01) after 3 and 6 months of treatment. No correlations with other endogenous hormones, proteins or with the two exogenous progestogens dienogest and norethisterone were observed. Increased breast cell proliferation should probably be regarded as an unwanted side-effect during HRT. Means to identify those women with the most pronounced proliferative response should be developed. The FNA biopsy technique may be a useful tool to monitor and evaluate the proliferative response to HRT in the normal breasts of postmenopausal women.

The effects of postmenopausal hormone replacement therapy and oral contraceptives on the endogenous estradiol metabolism.

The estradiol metabolism may be of clinical relevance in the pathophysiology of various diseases; the increase in D-ring metabolites over A-ring metabolites in breast cancer patients is of special interest. Since estrogen therapy has been blamed for increasing the risk of breast cancer, the effects of hormonal replacement therapy (HRT) and oral contraception were investigated on the ratio of the main D-ring metabolite, 16alpha-hydroxyestrone (16-OHE1), to the main A-ring metabolite, 2-hydroxyestrone (2-OHE1). In our study, hormone replacement therapy (HRT) in postmenopausal women consisted of administration of estradiol valerate either with or without addition of the progestin dienogest. In the second part of the study, women of reproductive age received ethinylestradiol plus dienogest or ethinylestradiol plus norethisterone acetate as oral contraceptives (OC). 2-OHE1 and 16-OHE1 were measured by enzyme immunoassay in 8 h night-urine collected before and after 3 months of hormone administration. With HRT, that is, estradiol valerate or estradiol valerate plus dienogest, the ratios before treatment were 0.47 and 0.60; after 3 months, they were 0.54 and 0.52, respectively. There were no significant differences. With oral contraception, that is, ethinylestradiol plus dienogest or norethisterone acetate, the ratios before administration were 0.62 and 0.68, vs. 0.31 and 0.54 after 3 months, respectively. The ratio after ethinylestradiol and dienogest was significantly lower after treatment. HRT and OC in the estrogen-progestin combinations tested did not impose any negative effects on estradiol metabolism--they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.

Effect on biochemical vasoactive markers during postmenopausal hormone replacement therapy: estradiol versus estradiol/dienogest.

OBJECTIVES: Aim was to compare the effects of estradiol-only therapy with combined estradiol/progestin treatment on the excretion of vasoactive mediators surrogating on possible effects in the vascular system. The progestin used was dienogest, a new C19-progestin with antiandrogenic properties. METHODS: Prospective, randomized trial, 25 healthy postmenopausal women treated for 3 months with estradiol valerate (2 mg/day) and 27 women with estradiol valerate (2 mg/day) continuously combined with dienogest (2 mg/day). Assessment of the following markers or their stable metabolites in nocturnal urine: cGMP, serotonin, prostacyclin and thromboxane, and urodilatin. RESULTS: Estradiol alone increased the excretion of cGMP and serotonin significantly suggesting vasodilating effects. The prostacyclin/thromboxane ratio known to be crucial for the relation of vasorelaxation to vasoconstriction significantly increased. No significant changes were found for urodilatin, which is known to elicit different effects in the cardiovascular and renal system, respectively. Combined estradiol/dienogest therapy also led to significant increases in cGMP and serotonin excretion suggesting that progestin addition for three months does not affect these markers. However, in contrast to estrogen-only treatment, there was no significant increase for the prostacyclin/thromboxane ratio, which can be explained by antagonistic action of the progestin. The excretion of urodilatin was increased significantly, which might be due to counterbalancing progestin effects in the renal vascular system. CONCLUSIONS: The changes in vasoactive markers suggest an estrogen effect that is vasorelaxant. Since there were no significant differences between the two groups, possible vascular effects of the progestin dienogest, for the first time evaluated, might not be of clinical relevance, at least not in women without cardiovascular diseases.

Double-blind, placebo-controlled psychometric studies on the effects of a combined estrogen-progestin regimen versus estrogen alone on performance, mood and personality of menopausal syndrome patients.

The influence of a combined estrogen-progestin regimen (Climodien) on noopsyche, thymopsyche, personality and psychophysiological measures of menopausal syndrome patients was investigated in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase (Climodien 2/3 = estradiol valerate (CAS 979-32-8) 2 mg + the progestin dienogest (CAS 65928-58-7) 3 mg = regimen A, estradiol valerate 2 mg = regimen EV, and placebo = regimen P) followed by an open-label phase in which all patients received Climodien 2/2 (estradiol valerate 2 mg + dienogest 2 mg) = regimen A*. 49 women (16, 17, 16 valid patients per arm) aged between 46 and 67 years (mean 58, 58, 56 years, respectively) with the diagnoses of insomnia (G 47.0) related to postmenopausal syndrome (N 95.1) were included in the analysis of the double-blind phase. Both the double-blind and the open-label phase lasted 2 months. Noopsychic investigations demonstrated an improvement in associative verbal memory after 2 months of regimen A, which was significant as compared with both baseline and placebo. Regarding visual memory, regimen A* induced an improvement, which was significantly different from the decline in correct reproductions in the Benton Test observed under estradiol. Errors in the Benton Test decreased significantly after regimen A* as compared with regimen EV. These findings suggest that hormone replacement therapy with estradiol, and even more in combination with dienogest, improves verbal and visual memory, which is in line with the improvement in information processing speed and capacity objectified by event-related potentials (ERP). Thymopsychic investigations demonstrated a significant improvement in somatic complaints and trait anxiety after both regimen A and regimen EV as compared with baseline. State anxiety decreased significantly under regimen A* as compared with EV. The Freiburger Personality Inventory showed an improvement in aggressivity after regimen A* as compared with the preceding placebo as well as an improvement in striving after dominancy after both regimen A and regimen EV as compared with pre-treatment, but also after regimen A* as compared with regimen EV. Extraversion increased after 2 months of regimen A as compared to regimen P. Psychophysiological findings including pupillary and skin conductance variables were not significant.

Climodien (estradiol valerate 2 mg plus dienogest 2 mg) is safe and effective in the treatment of postmenopausal complaints.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of continuous combined hormone replacement therapy (HRT) with Climodien (estradiol valerate 2 mg plus dienogest 2 mg). DESIGN: Open, multinational, multicenter, non-controlled phase III study. PARTICIPANTS: A total of 1501 women aged 52-65 years with postmenopausal symptoms of sufficient severity to require treatment. METHODS: Eligible patients were treated with Climodien for 12 treatment cycles (48 weeks), with assessments of efficacy, safety and tolerability (adverse events) at 8, 24 and 48 weeks. Efficacy was assessed using the Kupperman index. Safety assessments included endovaginal sonography, safety endometrial biopsies, mammography, physical and gynecological examination, vital signs, prothrombotic factors and routine laboratory safety parameters. RESULTS: The Kupperman index improved with increasing duration of treatment, accompanied by an improvement in self-reported patient well-being. Individual climacteric symptoms such as hot flushes and psychonervous disorders also improved. The most pronounced improvement was seen in women who had not previously used HRT. The incidence of breakthrough bleeding declined over time, resulting in complete amenorrhea in 86.2% of the patients after 12 cycles of treatment. Furthermore, total and low-density lipoprotein (LDL) cholesterol levels decreased and high-density lipoprotein (HDL) cholesterol levels increased. Decreases in alkaline phosphatase, pyridinoline and deoxypyridinoline demonstrated the inhibitory action of estradiol on bone resorption. Endometrial thickness remained almost constant, and the incidence of serious endometrial findings was similar to that in untreated women. CONCLUSIONS: Continuous combined estrogen-progestin therapy with Climodien is effective, safe and well tolerated in postmenopausal women, with a profile and incidence of adverse events consistent with those of existing HRT preparations.

Continuous-combined treatment of the menopause with combinations of oestradiol valerate and dienogest - a dose-ranging study.

OBJECTIVES: To determine the progestational efficacy of continuous treatment with various doses of dienogest, combined with oestradiol valerate, on the basis of endometrial histology, effect on climacteric symptoms and bleeding profile in postmenopausal women. METHODS: Patients were randomised to one of five fixed-combination treatments, oestradiol valerate 2.0 mg plus dienogest 0.5, 1.0, 2.0, 3.0 or 4.0 mg. Efficacy was assessed by endometrial biopsy, menstrual charts and change in climacteric symptoms. RESULTS: The endometrium was classified as atrophic in 20.0, 31.3, 25.0, 55.6 and 57.1% of patients in the 0.5, 1.0, 2.0, 3.0 and 4.0 mg dienogest groups, respectively. The frequency of uterine bleeding was dose-dependent. The most favourable bleeding profile was seen in the 3.0 mg dienogest group, whereas the lower doses of dienogest had advantages with respect to the efficacy of the combined preparation. CONCLUSIONS: Dienogest 2.0 and 3.0 mg are the optimal doses for combination with 2.0 mg oestradiol valerate for continuous-combined hormone replacement therapy.

Effect of oral contraceptives on the urinary excretion of biochemical markers indicating vasoactive action.

OBJECTIVE: In the present study the effect of two contraceptive pills, i.e. Neorlest, containing ethinylestradiol and norethisterone acetate, and Valette, containing ethinylestradiol and the new progestin dienogest, was investigated on the urinary excretion of vasoactive markers. As markers prostacyclin and its antagonist thromboxane, cGMP, serotonin, and the vasorelaxing mediators relaxin and urodilatin were measured. METHOD: 30 women received Neorlest and 33 women Valette in a randomized, open, parallel-group study design. Nocturnal urine was collected before treatment and during cyclic treatment after 6 and 11 weeks. RESULTS: For prostacyclin, the ratio of prostacyclin to thromboxane, relaxin and urodilatin significant increases compared to the pretreatment values were observed with Valette within 11 weeks treatment. For the markers cGMP and serotonin both contraceptive pills showed a tendency to an increase of the renal excretion after 11 weeks treatment. No significant differences between the two pills were observed, except in the case of the ratio of prostacyclin to thromboxane, which showed a significant, clear-cut enhancement with Valette. CONCLUSION: These results indicate that contraceptive pills may stimulate the production of vasodilative markers, an effect which can be attributed most likely to the oestrogenic component of the pill. 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.

A comparative study of the effects of two oral contraceptives containing dienogest or desogestrel on the human immune system.

The effects of two oral contraceptive combinations, dienogest 2.0 mg plus ethinyl estradiol 0.03 mg (Valette) and desogestrel 0.15 mg plus ethinyl estradiol 0.02 mg (Lovelle), on the human immune system were compared over one treatment cycle of 31 patients (n = 15 and n = 16, respectively). Lovelle but not Valette significantly increased the numbers of lymphocytes, monocytes and granulocytes. Valette decreased CD4 lymphocytes after 10 days' treatment; Lovelle had the opposite effect. Lovelle increased CD19 and CD23 after 21 days' treatment. Phagocytic activity was unaffected by either treatment. After 10 days' treatment, both contraceptives reduced serum IgA, IgG and IgM, which remained lowered at day 21 with Lovelle but returned to baseline with Valette. Secretory IgA was unaffected by either contraceptive. Neither treatment affected levels of interleukins, except for a significant difference between the treatment groups for interleukin-6 after 10 days' treatment that disappeared after 21 days' treatment. Levels of non-immunoglobulin serum components fluctuated; macroglobulin was increased with Valette. However, total protein and albumin levels were reduced more with Lovelle than with Valette. Complement factors also fluctuated. There was no evidence for any sustained immunosuppression with either Valette or Lovelle.

Comparison of the efficacy and endometrial safety of two estradiol valerate/dienogest combinations and Kliogest for continuous combined hormone replacement therapy in postmenopausal women.

OBJECTIVE: To compare the efficacy and endometrial safety of two estradiol valerate/dienogest combinations with Kliogest in the treatment of postmenopausal symptoms. DESIGN: This was a double-blind, randomized, multicenter study. METHODS: Patients were randomized to estradiol valerate 2.0 mg/dienogest 2.0 mg (Climodien), estradiol valerate 2.0 mg/dienogest 3.0 mg (E2Val 2/DNG 3); or estradiol 2.0 mg/estriol 1.0 mg/norethisterone acetate 1.0 mg (Kliogest) once daily for 1 year. The primary efficacy variable was the Kupperman index. Endometrial safety was determined primarily by biopsy. RESULTS AND CONCLUSIONS: Climodien and E2Val 2/DNG 3 were therapeutically equivalent to Kliogest (mean changes in Kupperman index -20.1, -19.0 and -18.3, respectively). No statistically significant differences existed between treatment groups in the severity of postmenopausal symptoms. The incidences of endometrial atrophy were similar in all groups. Climodien appeared to be superior to Kliogest in terms of vaginal bleeding pattern, whereas E2Val 2/DNG 3 was associated with a slightly higher incidence and greater intensity of vaginal bleeding. The incidences of adverse events were similar in all groups. A greater proportion of women in the Kliogest and E2Val 2/DNG 3 groups experienced vaginal bleeding, whereas breast problems were more common with Climodien. Climodien and E2Val 2/DNG 3 induced desirable changes in insulin-like growth factor I (decrease) and sex hormone binding globulin (increase) that were not seen with Kliogest.

Approaches to the replacement of ethinylestradiol by natural 17beta-estradiol in combined oral contraceptives.

The strong hepatic estrogenic actions of ethinylestradiol (EE) are very likely to be the cause of the cardiovascular morbidity related to the use of combined oral contraceptives (COCs). This survey presents results of EE replacement in COCs with natural 17beta-estradiol (E2) in the following stages: reduction of EE to daily doses of 0.01 mg and concomitant replacement with E2 (as valerate, EV), complete replacement of EE with E2 using a novel multiphasic combination containing EV and the progestin dienogest (DNG), and the use of natural E2 to develop estrogen sulfamates (J 995) showing sufficient dissociation of uterine from liver estrogenicity. Recent data from preclinical and clinical studies show that these approaches seem to be promising.

Evaluation of an oral pulsatile delivery system for melatonin in humans.

Using melatonin (MT) as a circadian synchroniser in humans to treat a variety of rhythm disorders, it is desirable to develop controlled-release dosage forms that deliver MT in accordance with its endogenous secretory pattern as well as preparations that release MT in a pulsatile way. In this paper we describe two oral pulsatile dosage forms containing 10 mg MT each (capsules B and C) and a fast-release form containing 5 mg MT (capsule A) studied in a randomised single-dose, threefold cross-over study in 15 healthy male volunteers. The concentrations of both MT in serum and its main metabolite 6-sulfatoxymelatonin (aMT6s) in urine were analysed by means of specific radioimmunoassays up to 10 h p.a. of the MT preparations. Mean peak concentrations of MT in serum were reached between 0.5 h and 0.75 h (Cmax[1] pmol/ml): 20.7 (A), 16.4 (B), 9.7 (C). The capsules B and C released a second MT pulse after about 3.5 h with Cmax[2] of 13.0 and 17.5 pmol/ml, respectively. Dose proportionality for the MT preparations studied was calculated by determining the AUC0-infinity (pmol/ml.h): 18.4 (A), 36.1 (B), 42.4 (C). The terminal serum half-lives of MT ranged between 0.64 and 0.84 h. The time course of the renally excreted aMT6s correlated with that of changes in MT serum concentrations.

Influence of hormonal contraceptives on microbial flora of gingival sulcus.

To determine a possible influence of two different hormonal contraceptives on bacterial microflora of gingival sulcus, subgingival plaque samples of 29 healthy women aged between 20 and 32 years were investigated bacteriologically before subjects took a contraceptive and 10 and 20 days after subjects started the medication. In 14 women, and oral contraceptive containing 0.02 mg ethinyl estradiol and 0.15 mg desogestrel (preparation A) was used, and 15 women took a contraceptive containing 0.03 mg ethinyl estradiol and 2.00 mg dienogest (preparation B) daily over 21 days. There were no changes in clinical parameters of the teeth investigated during 3 weeks of the study. The periodontopathogenic bacteria Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were never detected throughout the study. On the other hand, the periodontopathogenic species Prevotella intermedia was found in plaque samples of 22 women. The content of this microorganism showed only a little change between the pretreatment period and plaque sampling after 10 days of contraceptive treatment, but a striking increase occurred after 20 days of contraceptive treatment, especially in the preparation A group. In this respect, there was a significant difference between preparations A and B.

PIP: Several studies have suggested an association between sex hormones and chronic inflammatory periodontal disease. This study investigated the impact of two oral contraceptives (OCs) on bacterial microflora of gingival sulcus samples obtained from 29 women 20-32 years of age recruited from Jena (Germany) University Women's Hospital. Study participants were randomly assigned to receive an OC containing either 0.02 mg of ethinyl estradiol and 0.15 mg of desogestrel (n = 14) or 0.03 mg of ethinyl estradiol and 2.00 mg of dienogest (n = 15). Subgingival plaque samples were obtained before and 10 and 20 days after the initiation of OC use. No changes in clinical parameters of the upper incisors (i.e., bleeding on probing, pocket depth, plaque) occurred in either study group during 21 days of OC use. Although Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were not detected, 22 plaque samples showed evidence of the periodontopathogenic bacteria Prevotella intermedia. The mean cultivable content of this microorganism increased significantly in users of the OC containing desogestrel from 1.2% at day 10 of OC use to 10.0% at day 20, but decreased slightly in women assigned to the OC containing dienogest and a higher dose of ethinyl estradiol. Good oral hygiene is essential in pregnancy and during OC use to compensate for hormonal influences and prevent gingivitis.

Modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest.

Twenty-two healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.3 +/- 4.1), were included in a single-center, noncomparative study to investigate the modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest. At baseline, during three treatment cycles and post-treatment, serum levels of luteinizing hormone, follicle-stimulating hormone, 17 beta-estradiol, and progesterone were assayed and ultrasonography was used to measure follicular size and the thickness of the endometrium. The primary efficacy variable was inhibition of ovulation as measured by ovarian activity grading. All volunteers ovulated during the pretreatment cycle. During treatment, none of the subjects had ovulatory cycles, although there was still some ovarian activity in several subjects. During the first treatment cycle, only 4% (1 subject) of cycles showed active follicle-like structures. The frequency of follicle-like structures increased to 33% and 35% during treatment cycles 2 and 3. The frequency of presumptive luteinized unruptured follicle-like structures was 5% (1 subject) and 15% (3 subjects) in treatment cycles 2 and 3. The serum hormone concentrations were effectively suppressed in comparison to baseline. The ovarian activity returned to baseline during the post-treatment period. One subject was excluded from further study because of a medical problem believed unrelated to use of the oral contraceptive. No serious adverse events were recorded during the course of the study. 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.

Double-blind, randomized, placebo controlled study on the effects of the monophasic oral contraceptive containing 30 micrograms ethinyl estradiol and 2.00 mg dienogest on the hemostatic system.

Forty healthy female volunteers aged between 19 and 35 years (27.3 +/- 4.1 years) with normal menstrual cycles were included in a double-blind, randomized, placebo-controlled study to investigate the influence on the hemostatic system of an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest, which is a 19-norprogestin without a 17 alpha-ethinyl group. At baseline and during one treatment cycle, 12 hemostatic parameters were measured on cycle days 7, 14, and 21. The hemostatic parameters were categorized as either procoagulatory, anticoagulatory and profibrinolytic, or antifibrinolytic and indicative of fibrin turnover. Differences between placebo and 30 micrograms ethinyl estradiol and 2.00 mg dienogest of plasma levels of hemostatic parameters on cycle days 21 of the precycle and treatment cycle were chosen as target variables. Prothrombin fragment 1 + 2 (F 1 + 2) was chosen as the main target variable. Equivalence of F 1 + 2 between placebo and active treatment was noted. Among the procoagulatory factors, only factor VII activity was found to be increased over placebo in the active treatment group, but decreased in the placebo group. 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. There was a corresponding increase in fibrinolytic activity being reflected by higher plasminogen levels in the active treatment group in comparison with placebo. An increase was noted for the fibrinolytic parameter D-dimer. Apart from isolated measurements, the parameters remained in their respective normal ranges. The data combine to suggest that 30 micrograms ethinyl estradiol and 2.00 mg dienogest has a balanced effect on the hemostatic system stimulating both procoagulatory and fibrinolytic activity.

PIP: The influence on the hemostatic system of a monophasic oral contraceptive (OC) containing 30 mcg of ethinyl estradiol and 2 mg of the progestin dienogest was investigated in a double-blind, placebo-controlled study involving 40 healthy German women 19-35 years old. A total of 12 hemostatic parameters were measured on cycle days 7, 14, and 21 at baseline and during 1 treatment cycle. The prothrombin fragment 1 + 2 (an early and sensitive marker for the activation of hemostasis) was equivalent between OC users and untreated controls. Among the precoagulatory factors, only factor VII activity was not equivalent; on day 21, there was a decrease in the placebo group and an increase in the OC group. Also on day 21 of the treatment cycle, protein C activity increased in OC users compared to controls. There was a corresponding increase in fibrinolytic activity, reflected by higher plasminogen levels in OC users, and an increase in the fibrinolytic parameter D-dimer. In general, hemostatic parameters remained within their normal ranges. These findings confirm that the OC analyzed has a balanced effect on the hemostatic system, simultaneously stimulating both procoagulatory and fibrinolytic activity.

[Effect of ethinyl estradiol-dienogest combination on serum androgen concentrations]. / Der Einfluss einer Ethinylestradiol-Dienogest-Kombination auf die Serum-Androgen-Konzentrationen.

Antiandrogens or progestins with an antiandrogenic component usually have only a weak antigonadotropic activity. It is thus possible that the antiandrogenic effect on the cellular level is cancelled or at least reduced by an increased ovarian androgen production. The aim of the four submitted clinical studies of the progestin and antiandrogen dienogest alone (0.5-2 mg/day) or of a combined regimen of ethinylestradiol (0.03 mg) plus dienogest (2 mg) (EE/DNG) was to examine the influence on the serum androgen and SHBG concentrations as well as on the serum FSH, LH, progesterone and 17 beta-estradiol concentrations in young women. Like the progesterone derivatives, dienogest has a relatively low antigonadotropic activity. Inhibition of ovulation is mainly produced by peripheral mechanisms such as the reduction of preovulatory 17 beta-estradiol secretion. Dienogest alone has no significant effects on the serum SHBG and androgen concentrations. Unlike this, the combination of EE plus DNG markedly increases SHBG concentrations (to 2.1-3.7 fold the basal levels). The decrease in serum androgens with total testosterone (by 17 and 40%), free testosterone (by 48 and 54%) and dehydroepiandrosterone sulfate (by 51%) corresponds to the values shown in the literature for other oral contraceptives with modern progestins. EE/DNG does not affect the serum concentrations of 5 alpha-dihydrotestosterone (DHT), although the marker of the peripheral transformation from T to DHT, androstanediol glucuronide, is distinctly reduced (by 38%). In a double-blind comparison no differences are found between EE/DNG and a regimen combining 0.02 mg of ethinylestradiol and 0.150 mg of desogestrel. Solely the SHBG concentrations, with EE/DNG, as expected, are significantly higher. In a sequential regimen, dienogest, chlormadinone acetate and desogestrel (progestins without binding to SHBG) enhance the inhibitory effect of ethinylestradiol sulfonate on free testosterone, whereas norethindrone acetate and levonorgestrel (progestins with a strong binding to SHBG) reduce this effect of the estrogen significantly. These results exclude the possibility that the very distinct antiandrogenic effect of dienogest on a cellular level is neutralised or reduced by an increased systemic supply of androgen.

A comparative study of two levonorgestrel-containing hormone replacement therapy regimens of efficacy and tolerability variables.

OBJECTIVE: To compare the effect of two sequential hormone replacement regimens differing in the dose of levonorgestrel on climacteric symptoms, bleeding pattern and lipid metabolism in postmenopausal women. STUDY DESIGN: In a multicentre, randomized, double-blind, active-treatment-controlled study, 210 postmenopausal women were assessed at the end of treatment cycles 3 and 6. The high-levonorgestrel group was treated with 2 mg estradiol valerate (days 1-21) sequentially combined with 0.25 mg levonorgestrel (days 12-21). The low-levonorgestrel group received the same estrogen regimen (2 mg estradiol valerate, days 1-21), but levonorgestrel was administered sequentially in a dose of 0.15 mg during the last 12 days of the cycle (days 10-21). Statistical analysis by Student's t-test for dependent variables (measured values versus baseline) and independent variables (differences between groups), and the composite t-test method for comparison of both regimens with respect to efficacy, was performed. RESULTS: Both groups were statistically comparable. The trial was completed by 137 subjects. Protocol violations occurred in 38 cases. Thirty-five subjects dropped out during the study, 21 of them because of adverse events. Both treatments were equally effective in the treatment of climacteric complaints. There were no clinically significant changes in body weight, blood pressure, haematological tests, and parameters of clinical chemistry. There was a tendency towards a reduction in bleeding intensity in both groups in the second half of the treatment period. The treatment for six cycles with both regimens significantly (P < 0.05) decreased plasma concentrations of triglycerides (significant in the low-levonorgestrel group only), high-density lipoprotein cholesterol, high-density lipoprotein-3-cholesterol, lipoprotein(a) and apolipoprotein A1. In parallel, the serum concentration of total cholesterol increased significantly in both treatment groups, whereas low-density lipoprotein cholesterol increased significantly in the high-levonorgestrel group only. The changes in high-density lipoprotein-2-cholesterol, and apolipoprotein B did not reach statistical significance. CONCLUSIONS: It can be concluded that both sequential combined oral hormone replacement therapy (HRT) regimens were equivalent with respect to efficacy and tolerability in the treatment of women with climacteric complaints. The preparation with the lower dose of progestin showed a tendency towards a less unfavourable influence on the lipid profile.

Mechanisms of relaxation of rat aorta in response to progesterone and synthetic progestins.

OBJECTIVE: To compare the acute effects of progesterone, chlormadinone acetate (CMA), norethisterone acetate (NETA) and dienogest (DNG) with those of 17 beta-estradiol (17 beta-E2) on the vascular reactivity of male rat thoracic aorta. METHODS: Aortic rings with or without endothelium were placed in an organ bath for isometric tension recording. The integrity of the endothelium was assessed by the relaxant response of precontracted rings to acetylcholine (1 and 10 microM), which was diminished after mechanical removal of the endothelium. The concentrations of the steroid hormones were 0.01-10 microM. RESULTS: In vessels precontracted with phenylephrine (1 microM), CaCl2 (3 mM) or KCl (30 mM), progesterone, CMA and NETA (10 microM each) an endothelium-independent relaxation of 20-35% resulted, with a maximum response after 20-30 min, while DNG had a negligible effect in all experiments. The same concentration of 17 beta-E2 was twice as potent as the progestins. Indomethacin, the cyclooxygenase inhibitor and glibenclamide, an inhibitor of the ATP-sensitive potassium channels, did not affect the relaxant responses. The antagonists of progesterone receptors J 867 (1 microM) as well as of estrogen receptors ICI 182780 (1 microM) did not counteract the relaxation induced by progesterone and 17 beta-E2, respectively. Progesterone (10 microM) did not interfere with endothelium-dependent acetylcholine-induced relaxation of precontracted aortic rings. Pretreatment of the vessels with the hormones attenuated the maximal contractile response to phenylephrine. In the presence of verapamil (1 microM) or progesterone (10 microM) or 17 beta-E2 (1 and 10 microM) the concentration-response curves for calcium-induced contractions in K(+)-depolarized vessels were shifted to the right, with suppression of the maximum response. CONCLUSIONS: These studies suggest that in addition to 17 beta-E2 the progestins, progesterone, CMA and NETA caused a reduction of vascular tone, probably due to blockade of voltage-dependent and/or receptor-operated calcium channels.

Lactulose or paromomycin do not affect ammonia generation in the isolated perfused rat small intestine.

It has been hypothesized that the beneficial effect on hepatic encephalopathy of lactulose or neomycin might be exerted by their effect on intermediary glutamine metabolism and ammonia generation within enterocytes. We examined glutamine consumption and the production of alanine and ammonia (net substrate exchange in nmol min-1 g-1) in isolated vascularly and luminally perfused small intestine from rats with and without pretreatment with lactulose (2.0 g/kg) or paromomycin (60 mg/kg). Without pretreatment, 50 mM lactulose or 1 mM paromomycin were equally ineffective to significantly reduce the consumption of arterial glutamine (-92 +/- 5 vs. -80 +/- 6 vs. -71 +/- 6 for controls, lactulose, or paromomycin; mean +/- SEM, n = 6 each, n.s. by analysis of variance), and the production of alanine (41 +/- 3 vs. 44 +/- 3 vs. 61 +/- 7, n.s.) or ammonia (42 +/- 6 vs. 42 +/- 6 vs. 38 +/- 6, n.s.). Similarly, glutamine utilisation, and the release of alanine and ammonia were not different after pretreatment for 10 days. Also, both agents did not reduce glutamine absorption from the lumen (-170 +/- 9 vs. -171 +/- 6 vs. -219 +/- 25, n = 5 each) or the concomitant vascular release of metabolic products alanine (92 +/- 7 vs. 78 +/- 10 vs. 77 +/- 10 vs. 77 +/- 7, n.s.) and ammonia (73 +/- 6 vs. 69 +/- 7 vs. 65 +/- 8, n.s.). Our results do not support the hypothesis, that lactulose or paromomycin reduce ammonia generation by small intestinal mucosa through a specific effect on intermediary glutamine metabolism.

Pharmacokinetics of the gyrase inhibitor marbofloxacin: influence of pregnancy and lactation in sows.

Six pregnant sows were treated in early pregnancy, late pregnancy and during lactation. Marbofloxacin was administered (2 mg/kg body weight) intravenously and orally. The active drug concentration in the plasma was quantitated by use of high performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated by use of statistical moments. In lactating animals, the concentrations in milk were also determined by HPLC. Mean elimination half-life of the drug after oral administration was significantly shorter in lactating sows (5.74h) than that of the early pregnancy group (10.09h). Total body clearance was highest in the lactating sows (3.27 ml/minute.kg body weight). The volume of distribution was large in all physiological states studied indicating good tissue penetration. Bioavailability was about 80% in pregnant and lactating sows. Antimicrobial secretion in milk contributed greatly to marbofloxacin elimination. These results indicate an important influence of lactation on marbofloxacin pharmacokinetics in sows. Therefore, in such cases, marbofloxacin dose should be increased during lactation.