Prostatic fluid composition and semen quality in dogs with benign prostatic hyperplasia undergoing treatment with osaterone acetate.

Benign prostatic hyperplasia (BPH) may alter prostatic fluid biochemical composition causing reduced fertility. Osaterone acetate (OA) is an androgen receptor antagonist marketed for treatment of canine BPH. Little information exists on effects of OA administration on biochemical composition of canine prostatic fluid and its role on fertility. The aim of this research was to study biochemical composition of prostatic fluid and its role on semen quality in dogs with BPH undergoing treatment with OA. Eight intact, 5-11-year-old dogs with benign prostatic hyperplasia were treated orally with OA at a dose of 0.25-0.5 mg/kg once daily for seven days. Prostatic volume, semen evaluation and a biochemical analysis of prostatic fluid were performed on the day before treatment (D0), D60, D120, D180 and D240. A significant reduction (57% and 61%) of prostatic volume was observed at D60 and D120, respectively, and a significant reduction (20%) of normal spermatozoa was observed at D60 coincident with a significant increase of sperm tail defects, which disappeared during the course of the treatment. Prostatic fluid composition did not vary during the OA treatment except for zinc (Zn2+ ) with a significant increase at D120 and D180 correlated with the return to normal sperm values. In conclusion, canine Zn2+ prostatic fluid concentrations decrease during development of BPH and return to normal during treatment with OA. Zn2+ is an important electrolyte for semen quality, suggesting that oral Zn2+ supplementation might be considered a treatment to improve semen quality.

Comparison of change in body weight between contraception containing 30-µg ethinylestradiol/2-mg chlormadinone acetate or 30-µg ethinylestradiol/3-mg drospirenone: a randomised controlled trial.

Objectives: The aim of this study was to compare changes in body weight in women using a combined oral contraceptive (COC) consisting of 30-µg ethinylestradiol (EE) and 2-mg chlormadinone acetate (CMA) or a COC consisting of 30-µg EE and 3-mg drospirenone (DRSP).Methods: This randomised double-blind controlled trial (ClinicalTrials.gov NCT01608698) was conducted at a university hospital-based clinic in Thailand between June 2012 and September 2015. A total of 102 women were enrolled in the study, 99 of whom were randomised to EE/CMA (n = 45) or EE/DRSP (n = 54). Each participant was treated for six cycles. Body weight and other parameters as well as side effects were recorded at baseline and at the end of the third and sixth cycles of treatment.Results: A significant difference was observed in mean body weight change between the EE/CMA and EE/DRSP groups from both baseline to third cycle (0.51 ± 1.36 kg vs -0.43 ± 1.56 kg; p = .003) and baseline to sixth cycle (1.00 ± 1.84 kg vs -0.20 ± 2.23 kg; p = .013). The mean difference in body mass index and waist circumference had a similar trend to that of the mean difference in body weight. There was no significant difference in side effects between groups.Conclusion: A COC containing 30-µg EE/3-mg DRSP tended to confer a significantly more favourable change in body weight over a 6-month period compared with a COC containing 30-µg EE/2-mg CMA, which was associated with an increase in body weight.

The effects of osaterone acetate on clinical signs and prostate volume in dogs with benign prostatic hyperplasia.

A clinical trial was performed to evaluate the therapeutic efficacy of osaterone acetate (OSA) in the treatment of benign prostatic hyperplasia (BPH) in dogs. Osaterone acetate (Ypozane, Virbac) was administered orally at a dose of 0.25 mg/kg body weight once a day for seven days to 23 dogs with BPH. During the 28-day trial, the dogs were monitored five times for their clinical signs and prostate volume. The OSA treatment promoted rapid reduction of clinical scores to 73.2% on day 7 and to 5.9% on day 28 (p⟨0.05). Osaterone acetate induced the complete clinical remission in approximately 83.0% of the dogs on day 28. The prostate volume regressed to 64.3% of the pretreatment volume after two weeks of the treatment (p⟨0.05) and to 54.7% at the end of the trial (p⟨0.05). In conclusion, OSA quickly reduced clinical signs and volume of the prostate glands in dogs with BPH.

[Transient, secondary hypoadrenocorticism after treatment with delmadinone acetate (Tardastrex®) in a two year old male dog]. / Transienter, sekundärer Hypoadrenokortizismus nach Behandlung mit Delmadinonacetat (Tardastrex®) bei einem zwei Jahre alten Rüden.

INTRODUCTION: A two year old male Labrador Retriever was treated with delmadinone acetate because of benign prostatic hyperplasia. Four days after the injection the dog showed gastrointestinal signs and a progressive lethargy. In the hospital for small animals of the Justus-Liebig-University of Gießen an ACTH stimulation test was done and a secondary hypoadrenocorticism was diagnosed. The dog was treated with prednisolone in physiological dose for 14 weeks after the injection. The clinical symptoms stopped immediately. A new ACTH stimulation test some weeks later showed a completely normal adrenal function.

DIAGNOSIS AND MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA IN A PIED TAMARIN (SAGUINUS BICOLOR).

An intact male pied tamarin (Saguinus bicolor) presented with a hunched posture while moving, dysuria, pollakiuria, and hematuria. After diagnostic imaging assessment and prostate biopsy, benign prostatic hyperplasia was diagnosed. Treatments with delmadinone acetate and osaterone caused clinical signs and hematuria to resolve temporarily for a variable period of time. Because of frequent recurrence, elective surgical castration was performed, leading to resolution of the clinical signs.

Extended cycles with the combined oral contraceptive chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg: pooled analysis of data from three large-scale, non-interventional, observational studies.

BACKGROUND AND OBJECTIVE: The prescribing of extended regimens of oral contraceptives (OCs) is increasing in routine gynaecological practice as a means of reducing the number of annual menstrual bleeds. Typically, this involves taking one pill per day for, say, 84 days continuously (4×21 days), followed by a 7-day pill-free interval. Low-dose OCs are suitable for extended use, and many gynaecologists in Germany prescribe the combination of chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg (CMA 2 mg/EE 0.03 mg). The aim of the current study was to assess the risks and benefits of CMA 2 mg/EE 0.03 mg in extended regimens, using pooled data from observational studies. METHODS: This pooled analysis of three large-scale, non-interventional, observational studies assessed the results in women receiving Belara® (CMA 2 mg/EE 0.03 mg) according to an extended regimen compared with conventional regimens documented in the summary of product characteristics. RESULTS: A total of 625 women were identified as extended-regimen users (mean±SD age 24.9±9.0 years). Extended-cycle use was associated with decreases in skin problems, dysmenorrhoea symptoms (as shown by reductions in analgesic use; absence from school, university, or work; and restrictions in leisure and sporting activities), cycle-dependent symptoms (e.g. headache/migraine, breast tenderness), withdrawal bleeding, bleeding duration and reduced libido. Mean bodyweight remained almost constant over 6 months. Only nine adverse drug reactions, none severe, were reported in eight women (1.3%). CONCLUSION: This pooled analysis confirms that extended regimens of CMA 2 mg/EE 0.03 mg reduce cycle-related complaints and are very well tolerated.

Efficacies of osaterone and delmadinone in the treatment of benign prostatic hyperplasia in dogs.

A multicentre randomised clinical trial was performed to compare the therapeutic potential of osaterone acetate with that of delmadinone acetate in the treatment of benign prostatic hyperplasia in dogs. The osaterone was administered orally at 0.25 mg/kg bodyweight once a day for seven days to 73 dogs. The delmadinone was administered by a single intramuscular or subcutaneous injection at 3 mg/kg bodyweight to 69 dogs. During the 180-day trial, the dogs were monitored five times for their clinical signs and prostate volume. The two drugs were similarly effective in reducing the clinical signs and inducing complete clinical remission, and both induced a similar level of minor, mostly transitory adverse effects. Osaterone reduced the volume of the prostate glands of the dogs significantly more quickly than delmadinone.

Metabolism of osaterone acetate in dogs and humans.

Osaterone acetate (17 alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione; OA) is a steroidal antiandrogen. In order to clarify the species differences, metabolites of OA were examined in plasma, urine, and feces of dogs and humans after oral administration of OA. Eleven metabolites in plasma, urine, and feces were identified by their spectral properties and comparison to appropriate standards. The primary routes of OA metabolism involve 11 beta-, 15 beta- and 21-hydroxylation, 17 alpha-deacetylation, and dechlorination. Other metabolites arise from combinations of these pathways to form multiple oxidized metabolites. All metabolites observed in humans occurred in dogs. 11 beta-Hydroxylated metabolites (11 beta-OH OA and 11-oxo OA) were found in the plasma and urine of dogs, but there was no evidence of their presence in humans. 11 beta-Hydroxylation of exogenous steroids represents a distinctive biotransformation pathway.

A new synthetic steroid, osaterone acetate (TZP-4238), increases cortical bone mass and strength by enhancing bone formation in ovariectomized rats.

A new synthetic steroid, 17 alpha-acetoxy-chloro-2-oxa-4,6-pregnadiene-3,20-dione (osaterone acetate, TZP-4238), has a potent antiandrogenic and gestagenic action with virtually no estrogenic and androgenic activity in their classical target organs. In the present study, the effects of TZP-4238 on the structure, strength, and turnover of the rat long bones were examined. Female Wistar rats at 12 weeks of age were ovariectomized (OVX) and treated with TZP-4238 or 17 beta-estradiol (E2) every day for 12 weeks. TZP-4238 significantly increased the diameters and maintained bone mineral density (BMD) of the femur of OVX rats. Although the BMD of the total femur was higher in E2-treated rats than that in TZP-treated rats, E2 did not increase the diameters of the femurs. To examine the effects of TZP-4238 and E2 on the BMD of different regions of the femur, the BMD was further analyzed by dividing it into 20 regions of equal longitudinal length. E2 increased the BMD of the distal and proximal metaphysis, regions rich in trabecular bone, but had no effect on the BMD of the femoral diaphysis compared with OVX control rats. In contrast, 2.5 and 12.5 mg/kg TZP-4238 increased the BMD of the femoral diaphysis, regions rich in cortical bone, but did not affect the BMD at the distal metaphysis. In agreement with the changes in the BMD of different regions of the femur, TZP-4238 but not E2 increased the physical strength of the femoral diaphysis assessed by a three-point bending test. Histomorphometric analyses of the cross-sections of the tibia revealed that TZP-4238 increased but E2 reduced the periosteal bone formation rate compared with OVX rats. In addition, TZP-4238 caused an increase in serum bone alkaline phosphatase with only a mild and transient decrease in urinary deoxypyridinoline excretion, while E2 reduced both of these parameters. These results demonstrate that TZP-4238 increases the dimension, BMD, and physical strength of the rat long bones by enhancing cortical bone formation, while estrogen maintains trabecular BMD by inhibiting bone resorption. Because the physical strength of long bones is affected by cortical bone mass and geometry, the effect of TZP-4238 on cortical bone may have a potential for the treatment of osteoporosis with reduced cortical bone formation.

Ethinylestradiol/chlormadinone acetate.

Ethinylestradiol/chlormadinone acetate 0.03/2mg (EE/CMA) is a combined monophasic contraceptive pill with antiandrogenic properties. In a large, noncomparative, multicentre trial (< or =24 cycles of treatment per woman) and two (6- and 12-cycle) postmarketing surveillance studies, EE/CMA was effective in preventing pregnancy. EE/CMA was significantly more effective than EE/levonorgestrel 0.03/0.15 mg/day in treating women with mild-to-moderate papulopustular acne of the face and related disorders in a randomised, single-blind, multicentre trial. EE/CMA was well tolerated in clinical trials and the postmarketing surveillance studies. Adverse events were those commonly reported with oral contraceptives. As expected, the most common menstrual disturbances were breakthrough bleeding, spotting and amenorrhoea.

Characterizations of mouse hepatic microsomal monooxygenase catalyzing 11beta-hydroxylation of osaterone acetate.

Osaterone acetate (17alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione, OA) is a new steroidal antiandrogen. There is a marked species difference in the metabolism of OA in that 11beta-hydroxylated metabolites are found in the plasma, feces, and urine of mice after oral administration of OA, but there is very little metabolism in rats and humans. OA reduces the adrenal gland weight in mice, but not in rats, and this effect in mice might be explained by the species difference in 11beta-hydroxylation activity. The objectives of this study were to elucidate the enzyme(s) involved in this particular oxidation and to explain the species difference observed. Mouse hepatic microsomes oxidize OA to 11beta-OH OA, and this oxidation requires NADPH as a cofactor. The use of various competitive and allosteric inhibitors of cytochrome P450 and flavin-containing monooxygenase (i.e. CO, N-octylamine, and methimazole) showed that the oxidation of OA was catalyzed by cytochrome P450. In microsomes from mice pretreated with phenobarbital (a CYP2B-selective inducer), 3-methylcholanthrene (a CYP1A-selective inducer), pregnenolone-16alpha-carbonitrile (a CYP3A-selective inducer), and EtOH (a CYP2E-selective inducer), an increase in the rates of oxidation was seen only in microsomes from EtOH-treated animals. However, metyrapone, a selective inhibitor for enzymes of the cytochrome P45011B and P4502B family, inhibited mouse hepatic microsomal 11beta-hydroxylation by < 30%. The results obtained showed that the production of 11beta-OH OA may be catalyzed by a novel cytochrome P450 in mouse liver.

Respiratory stimulation by female hormones in awake male rats.

The respiratory effect of progestin differs among various animal species and humans. The rat does not hyperventilate in response to exogenous progestin. The present study was conducted to determine whether administration of combined progestin and estrogen prompts ventilatory stimulation in the male rat. Ventilation, blood gases, and metabolic rates (O2 consumption and CO2 production) were measured in the awake and unrestrained male Wistar rat. The combined administration of a synthetic potent progestin (TZP4238) and estradiol for 5 days significantly increased tidal volume and minute expiratory ventilation (VE), reduced arterial PCO2, and enhanced the ventilatory response to CO2 inhalation (delta VE/delta PCO2). On the other hand, respiratory frequency, O2 consumption, CO2 production, and body temperature were not affected. The arterial pH increased slightly, with a concomitant decrease in plasma [HCO3-]. Administration of either TZP4238 or estradiol alone or vehicle (Tween 80) had no effect on respiration, blood gases, and ventilatory response to CO2. The results indicated that respiratory stimulation following combined progestin plus estradiol treatment in the male rat involves activation of process(es) that regulate tidal volume and its augmentation during CO2 stimulus.

Ovulation induction: ovarian response to human gonadotropins and synthetic gonadotropin-releasing hormone.

Human ovarian responses to FSH- and LH-releasing hormone (FSH/LH-RH) were observed at laparotomy and studies by histologic and histochemical examination of ovarian biopsy specimens. The responses were compared to those induced by human menopausal gonadotropin (HMG) and human chorionic gonadotropin (HCG) singly and together. The subjects were healthy, fertile, young women rendered anovulatory by injections of depomedroxyprogesterone acetate (DMPA) or depochlormadinone acetate (CA). Supplementary studies included measurement of urinary pregnanediol, examination of the cervix and vagina for estrogenic and progestational responses, and endometrial biopsy, Both HMG and HCG induced follicular growth and proliferation of granulosa and theca cells, but neither, when given alone, induced ovulation or corpus luteum formation. When given in conjunction they induced single or multiple ovulations and corpora lutea in 11 of 18 women treated. FSH/LH-RH CONSISTENTLY STIMULATED FOLLICULAR DEVELOPMENT AND INDUCED OVULATION IN 2 OF 16 WOMEN TREATED. Preovulatory mature follicles were found in 3 more. FSH/LH-RH may prove to be useful in the treatment of some cases of anovulatory sterility of hypothalamic origin.

Implant pellets I: effects of compression pressure on in vivo dissolution of delmadinone acetate pellets.

A formulation containing 95% delmadinone acetate was compressed at three different pressures. These pressures resulted in a pellet density difference of 19%. In vivo dissolution profiles were determined for five lots of pellets. The pellets were implanted subcutaneously in rats, removed periodically, and assayed chemically for remaining steroid. The resulting data were fit, using the computer program NONLIN, to a dissolution model. The dissolution rate for the lot with the lowest density made at the lowest compression was statistically (p less than 0.05) different from the four other lots. A possible explanation for this increased dissolution rate could be that channeling occurs within the pellet, thereby increasing the effective dissolving surface. The results also indicate that equivalent dissolution rates between lots are reached at a certain compression and density.

PIP: Effects of compression pressure on in vivo dissolution of delmadinone acetate implant pellets were investigated in rats. A formulation containing 95% delmadinone acetate was compressed at 3 different pressures which resulted in a pellet density difference of 19%. Pellets from 5 different lots were implanted sc, removed periodically, and assayed chemically for remaining steroid. The results were fit, using the computer program NONLIN, to a dissolution model. The dissolution rate for the lot with the lowest density made at the lowest compression was significantly (p less than .01) greater than that of the other 4 lots. A possible explanation could be that channeling occurs within the pellet, thereby increasing the effective dissolving surface. These results also suggest that equivalent dissolution rates between lots are reached at a certain compression and density.

Metabolic changes in women using a long-acting monthly oral contraceptive and return of ovulation on discontinuation.

Metabolic changes were investigated in two groups of women using oral contraceptives for 5 to 16 years. Blood samples were taken during the last cycle of oral contraceptive use and three months post-treatment. One group had used a monthly oral contraceptive (MOC, 3mg quinestrol and 10mg 16-methylene chlormadinone acetate) and the second group a daily oral contraceptive (DOC, 35 micrograms ethynylestradiol and 0.625 mg norethisterone). During treatment there were increases in serum total cholesterol and triglycerides but not HDL-C, in plasma total cortisol but not in renin activity, angiotensin II or urinary free cortisol excretion, in hemoglobin and some coagulation factors but not Factor X or antithrombin III, platelet function or fibrinolysis. The area under the blood glucose concentration-time curve, but not that for serum insulin, was slightly increased and there was no change in fasting blood sugar concentrations. All metabolic parameters, except plasma cortisol, which had shown an increase on treatment, had decreased to control levels within 3 months. Ovulation returned promptly in all women, the mean time being 70 days for Group MOC and 44 days for Group DOC. Thus, in spite of the long duration of use of the oral contraceptives, metabolic changes were minor.

Regression of prostatic hypertrophy by osaterone acetate in dogs.

The prostatic regression effect of oral administration of a new steroidal anti-androgen, osaterone acetate, was investigated in dogs with prostatic hypertrophy. To dogs with prostatic hypertrophy, 0.1-1.0 mg/kg of osaterone acetate was orally administered for one week, and the regression rate was observed. It was shown that administration of osaterone acetate at 0.2 mg/kg or higher, sharply regressed prostatic hypertrophy during the early stage. Therefore, this agent may be clinically applicable as a therapeutic agent for benign prostatic hypertrophy.

Effect of osaterone acetate administration on prostatic regression rate, peripheral blood hormone levels and semen quality in dogs with benign prostatic hypertrophy.

The effects of osaterone acetate (OSA), which is an anti-androgen agent being developed as a therapeutic drug for benign prostatic hypertrophy (BPH) in dogs, on the degree of prostatic regression and semen qualities were investigated. Prostatic regression was compared between dogs with and without orchidectomy. Five male beagles aged 5-9 years were used in the experiment. OSA was orally administered at doses of 0.2 mg/kg and 0.5 mg/kg for one week. The prostatic regression rate one week after the end of administration was 62.6% on average. In the orchidectomized group, the mean regression rate one week after orchidectomy was 60.1%. However, the prostate became enlarged 6 months after administration, compared to the size prior to administration. The above findings suggested that OSA is clinically applicable as a therapeutic drug for BPH in dogs, and inhibits prostatic hypertrophy during the early phase.

[Synthesis of chlormadinol acetate-3-beta-O-alpha-1-arabinofuranosides with positive inotropic action]. / Synthese des Chlormadinolacetat-3 beta-O-alpha-L-arabinofuranosids mit positiv inotroper Wirkung.

The synthesis of chlormadinol acetate-3 beta-O-alpha-L-arabinofuranoside (3; 17 alpha-Acetoxy-6-chloro-pregna-4,6-diene-20-one-3 beta-O-alpha-L- arabinofuranoside) is described. Glycosidation of chlormadinol acetate (1) was accomplished with excess 2,3,5-tri-O-benzyl-alpha-L-arabinofuranosyl chloride, Fétizon reagent, mercury cyanide and bromide in toluene at room temperature. Debenzoylation into compound 3 was carried out with methanol/methylen chloride saturated with ammonia at low temperature. Surprisingly, substance 3 shows positive inotropic effects on cats in vivo, whereas the aglycone 1 produces negative inotropy.

Effects of delmadinone acetate on pituitary-adrenal function, glucose tolerance and growth hormone in male dogs.

OBJECTIVE: To characterise the effects of delmadinone acetate on the pituitary-adrenal axis, glucose tolerance and growth hormone concentration in normal male dogs and dogs with benign prostatic hyperplasia. DESIGN: A prospective study involving nine normal male dogs and seven with prostatic hyperplasia. PROCEDURE: Delmadinone acetate was administered to six normal male dogs and seven dogs with benign prostatic hyperplasia at recommended dose rates (1.5 mg/kg subcutaneously at 0, 1 and 4 weeks). Three normal controls received saline at the same intervals. Blood concentrations of ACTH, cortisol, glucose, insulin and growth hormone were measured over 50 days. Intravenous glucose tolerance and ACTH response tests were performed before and after treatment in the nine normal animals. RESULTS: A substantial suppression of basal and 2 h post-ACTH plasma cortisol secretion was demonstrated after one dose in all dogs given delmadinone acetate. Individual responses after the second and third administration varied between recovery in adrenal responsiveness to continued suppression. Plasma ACTH concentration was also diminished after one treatment. No effects were evident on glucose tolerance or serum growth hormone concentrations. CONCLUSION: Delmadinone acetate causes adrenal suppression from inhibition of release of ACTH from the pituitary gland. Treated dogs may be at risk of developing signs of glucocorticoid insufficiency if subjected to stressful events during or after therapy. Neither glucose intolerance nor hypersomatotropism seems likely in male dogs given delmadinone acetate at the recommended dose rate, but the potential for excessive growth hormone secretion in treated bitches remains undetermined.

[Catecholamine blood levels in sheep during superovulation in estrus]. / Hladiny katecholamínov v krvnej plazme oviec v estrickom období pocas superovulácie.

The effects of a serum gonadotropin (SG) superovulation hormonal preparation were investigated on catecholamine levels (norepinephrine, dopamine and epinephrine) in the blood plasma of ewes with synchronized oestrus in the oestrus period. In this trial the blood plasma of eleven ewes of the Slovak Merino breed was analyzed to detect catecholamines in the oestrus period. Superovulation was induced by an i.m. administration of 1500 IU SG as soon as oestrus synchronization with Agelin vaginal tampons finished (20 mg chlorsuperlutin) which lasted for 10 days. Catecholamines were detected in the blood plasma before synchronization, on the day of Agelin vaginal tampons application, and in 48 and 72 hours after the hormone administration--on the days of the expected ovulation. Catecholamine concentrations in the blood plasma were determined by a radioenzymatic assay using a Catechola test (Praha). The results indicate that synchronization and hormonal stimulation influence plasma catecholamine levels. The norepinephrine (NE) concentration in the blood plasma of the control samples has the value of 8.31 +/- 0.732 pmol/ml. An insignificant increase in the NE levels (13.12 +/- 0.120 pmol/ml; Fig. 1) was recorded on day 1 of the trial, after the start of synchronization. On the day of the expected ovulation the NE concentrations rose to 17.12 +/- 1.289 pmol/ml (P less than 0.001) and they remained significantly increased (P less than 0.01) at the level of 12.89 +/- 1.020 pmol/ml on the following day of the experiment. The dopamine level (DA) in the plasma of a control sample is 6.42 +/- 0.350 pmol/ml (Fig. 2).(ABSTRACT TRUNCATED AT 250 WORDS)