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.

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.

The effects of 2 mg chlormadinone acetate/30 mcg ethinylestradiol, alone or combined with spironolactone, on cardiovascular risk markers in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine disorder associated with metabolic dysfunction and changes in cardiovascular risk markers, and using oral contraceptives (OCs) may exert a further negative effect on these alterations in patients with PCOS. Thus, the primary objective of this study was to assess the effects on arterial function and structure of an OC containing chlormadinone acetate (2 mg) and ethinylestradiol (30 mcg), alone or combined with spironolactone (OC+SPL), in patients with PCOS. STUDY DESIGN: This was a randomized, controlled clinical trial. Fifty women with PCOS between 18 and 35 years of age were randomized by a computer program to use OC or OC+SPL. Brachial artery flow-mediated vasodilation, carotid intima-media thickness and the carotid artery stiffness index were evaluated at baseline and after 6 and 12 months. Serum markers for cardiovascular disease were also analyzed. The intragroup data were analyzed using analysis of variance with Tukey's post hoc test. A multivariate linear regression model was used to analyze the intergroup data. RESULTS: At 12 months, the increase in mean total cholesterol levels was greater in the OC+SPL group than in the OC group (27% vs. 13%, respectively; p=.02). The increase in mean sex hormone-binding globulin levels was greater in the OC group than in the OC+SPL group (424% vs. 364%, respectively; p=.01). No statistically significant differences between the groups were found for any of the other variables. CONCLUSION: The addition of spironolactone to an OC containing chlormadinone acetate and ethinylestradiol conferred no cardiovascular risk-marker advantages in young women with PCOS.

Evaluation of efficacy, safety and effects on symptoms of androgenization of a generic oral contraceptive containing chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg.

BACKGROUND: This prospective noninterventional study assessed the contraceptive efficacy, safety and the effects on signs of androgenization of the generic oral contraceptive containing 2 mg chlormadinone acetate/0.03 mg ethinylestradiol (CMA/EE) in a real-world setting. STUDY DESIGN: A total of 1440 women were investigated during a six-cycle period by 229 gynecological practices throughout Germany. RESULTS: The adjusted Pearl index was 0.136 (unadjusted: 0.271). Of 463 patients with cycle irregularities at baseline, 83.4% had regular cycles after six cycles. Likewise, 74.1% of 162 patients with spotting or breakthrough bleeding at baseline were free from these symptoms at the end of study. The percentage of patients with dysmenorrhea decreased significantly from baseline (36.5%) to visit 3 after six cycles (12.3%; p=.0001), with a significant reduction in the use of pain medication (p<.0001). Additionally, the number of patients with skin and hair problems was significantly reduced (skin: 56.3% at baseline, 19.6% after six cycles; hair: 45.7% at baseline, 13.4% after six cycles; p=.001). CMA/EE was well tolerated by the patients, and 89.44% of the gynecologists were satisfied with the treatment. CONCLUSION: Generic CMA/EE exhibits very good contraceptive efficacy, cycle control and dysmenorrhea reduction. Furthermore, treatment with generic CMA/EE led to a favorable reduction of skin and hair problems in our study.

Ethinylestradiol/Chlormadinone acetate: dermatological benefits.

Acne vulgaris, hirsutism, seborrhea and female pattern hair loss (FPHL) are common disorders of the pilosebaceous unit (PSU). In some women with hyperandrogenemia, an excess of androgens at the PSU can lead to the development of these dermatological manifestations. These manifestations can cause many psychiatric and psychological implications, such as social fears and anxiety, and can adversely affect quality of life. High androgen levels at the PSU as a possible underlying cause of acne vulgaris, hirsutism, seborrhea and FPHL supports the rationale for using combined oral contraceptives for the management of these conditions in women. The purpose of this review is to describe these dermatological manifestations of the PSU and the management of these conditions through the use of the oral contraceptive ethinylestradiol/chlormadinone acetate (EE/CMA). EE/CMA 0.03/2 mg is a combined monophasic contraceptive pill with anti-androgenic properties. It is approved in Europe for contraception and has been investigated in phase III trials for the treatment of acne. EE/CMA was better than placebo and similar to another low-dose oral contraceptive (ethinylestradiol/levonorgestrel) in improving symptoms of acne in two phase III randomized controlled trials in patients with mild to moderate papulopustular acne. In addition, in trials investigating the contraceptive efficacy of EE/CMA, limited data suggest that there were also improvements in hirsutism, FPHL and seborrhea in small subgroups of patients. EE/CMA has a good safety profile. The most commonly reported adverse events are breast tenderness/pain, headache/migraine and nausea. Evidence in the literature indicates that the use of EE/CMA for the treatment of dermatological disorders under the control of androgens may be a valid treatment option. Further investigation is warranted.

Ethinylestradiol/Chlormadinone acetate for use in dermatological disorders.

The diagnosis and management of four cases of dermatological disorders, most of which are related to the endocrine disorder of androgen excess, are presented. Combined oral contraceptives (COCs) may be useful when well-tolerated hormonal therapy and/or when contraception is required. A female patient with androgenetic alopecia or female pattern balding, without underlying hyperandrogenism, was treated with ethinylestradiol/chlormadinone acetate (EE/CMA) 0.03 mg/2 mg for 6 months and experienced stabilization of hair loss (case report 1). A patient who had previously received a COC for an irregular menstrual pattern but again experienced irregular menses and also acne after stopping treatment was diagnosed with acne associated with polycystic ovary syndrome (PCOS) [case report 2]. After 6 month's treatment with EE/CMA 0.03 mg/2 mg, this patient had fewer acne lesions and became eumenorrheic. A third patient who had excess hair since childhood was diagnosed with idiopathic hirsutism (no underlying gynecological or endocrinological disorder was found) and was treated with EE/CMA 0.03 mg/2 mg (case report 3). Less hair growth was reported after 6 months' treatment. Case report 4 describes a patient who presented with oligomenorrhea and acne. She was diagnosed with PCOS with acne, seborrhea and mild hirsutism. Treatment with EE/CMA 0.03 mg/2 mg for 6 months resulted in improvements in her facial acne, seborrhea and hirsutism; she also became eumenorrheic. These four cases illustrate that EE/CMA may be a useful and well tolerated treatment option in the management of patients with dermatological disorders with or without hyperandrogenization.

Ethinylestradiol-chlormadinone acetate combination for the treatment of hirsutism and hormonal alterations of normal-weight women with polycystic ovary syndrome: evaluation of the metabolic impact.

This is the first study evaluating the clinical, metabolic, and hormonal effects of the ethinylestradiol-chlormadinone acetate (EECMA) combination in hirsute women with polycystic ovary syndrome (PCOS). Ultrasonographic pelvic examination, hirsutism score, and hormone profile evaluation were performed at baseline and after 3 and 6 cycles of treatment. Oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, and assessment of lipid profile were carried out at baseline and after 6 cycles of treatment. A significant improvement in hirsutism was evident at the end of treatment. From the third cycle onward, plasma levels of sex hormone binding globulin significantly increased when compared to baseline. Free androgen index, androstenedione, and 17-hydroxyprogesterone significantly decreased after 6 cycles. The treatment did not affect glucose and insulin homeostasis. Total cholesterol, triglycerides, and high-density lipoprotein (HDL) plasma levels remained unvaried, whereas low-density lipoprotein (LDL) concentrations showed a significant reduction. A significant increase in very-low-density lipoprotein (VLDL) levels was seen at the sixth cycle of therapy. In conclusion, EE-CMA combination ameliorates clinical and hormonal features of PCOS women, with no detrimental effects on glucose, insulin, and lipid metabolism.

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.

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.

[Treatment of fibroepithelial hyperplasia (FEH) of the mammary gland in the cat with the progesterone antagonist Aglépristone (Alizine)]. / Der Progesteronantagonist Aglépristone (Alizine) zur Behandlung der fibroepithelialen Hyperlasie der Mamma bei der Katze.

Three cases of fibroepithelial hyperplasia (FEH) of the mammary gland in the cat are reported. A one year old female cat had a distinct enlargement of the middle mammary glands, one on each side, 5 days after the first estrus. One week later the cat was treated with medroxyprogesterone acetate (Depo-Promone). The affected glands, along with the remaining glands, increased further in size. A five year old female cat was treated with Proligeston (Covinan) for the suppression of estrus. Two weeks later fibroepithelial hyperplasia occurred in two glands, one with a well demarcated ulceration. A seven months old male cat was treated with delmadinon acetate (Tarden) because of urine spraying. Two months later he had enlargement of all mammary glands. All three cats were treated with the progesterone antagonist Aglépristone (Alizine). Within 5 to 11 weeks the mammary glands had regressed to normal.

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.

[Long-term survival of hormone-refractory prostate cancer: a case report].

Although prostate cancer initially responds well to endocrine therapy, it becomes resistant to the therapy a few years later, and is called hormone-refractory cancer. In general, hormone-refractory prostate cancer is resistant to all kinds of therapy and the prognosis is extremely poor. Here we report an unusual case of a person with hormone-refractory prostate cancer, who has been surviving for more than 5 years after being diagnosed as having this type of cancer. A 75-year-old man was diagnosed with prostate cancer (poorly differentiated adenocarcinoma, T3 N0 M1, stage D2) and initial endocrine therapy combined with castration and estrogen was effective. Four years later, the tumor marker of prostate-specific antigen (PSA) increased and the cancer was thought to be hormone-independent, refractory state. Alteration of antiandrogen from chlormadinone acetate to flutamide was effective and PSA was kept at low levels for 6 months. When PSA rose again, we started oral chemotherapy with tegafur.uracil. PSA decreased to normal range (complete response) and remained stable for 10 months. After that, a rapid increase of PSA was controlled for 7 months by oral chemotherapy with estramustine phosphate sodium and VP-16. This case indicates that alteration of antiandrogens or oral chemotherapy may be useful in some cases with hormone-refractory prostate cancer.

Determination of concentrations of sex steroids in blood plasma and semen of male dogs treated with delmadinone acetate or finasteride.

The concentrations of testosterone, 5 alpha-dihydrotestosterone, oestradiol and oestrone were determined in peripheral blood plasma and semen of male dogs. In an experimental study, three Beagles were treated once with delmadinone acetate (1 mg kg-1 body weight, i.m.) and three were submitted to oral applications of finasteride (1 mg kg-1 body weight) once a day for 3 weeks. In a clinical study, 51 dogs of different breeds were divided into four groups according to the total number of spermatozoa in ejaculates (normospermia, slight oligozoospermia, severe oligozoospermia and azoospermia). The testosterone concentrations were significantly lower in sperm-rich ejaculate fractions and prostatic secretions compared with blood plasma (P < 0.05). The lowest concentration of testosterone was found in prostatic fluid. Concentrations of 5 alpha-dihydrotestosterone were similar in blood plasma and sperm-rich fractions, and significantly lower in prostatic secretions (P < 0.05). The concentrations of oestradiol and oestrone did not differ between blood plasma and either ejaculate fraction. Significantly higher 5 alpha-dihydrotestosterone concentrations and significantly lower concentrations of oestradiol and oestrone were found in prostatic secretions from azoospermic ejaculates compared with prostatic secretions of normospermic and oligozoospermic ejaculates. Delmadinone acetate and finasteride caused reversible suppression of the secretory activity of the prostate gland. The application of delmadinone acetate led to a temporary alteration of maturation of epididymal spermatozoa.

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.

A prospective randomized multicenter study of chlormadinone acetate versus flutamide in total androgen blockade for prostate cancer.

BACKGROUND: A randomized multicenter study was conducted to investigate the efficacy of total androgen blockade (TAB) for patients with previously untreated prostate cancer using the steroidal anti-androgen chlormadinone acetate (CMA) and the non-steroidal anti-androgen flutamide. We also compared the liver dysfunction in these two arms. METHODS: From November 1995 to October 1997, 71 patients were registered into this study and 70 of them were eligible. RESULTS: There was no significant difference in the efficacy of TAB between CMA and flutamide at 24 weeks. The testosterone and prostate-specific antigen (PSA) levels in patients administered flutamide (Group II) increased significantly 3 days after the first dose of LH-RH analog, whereas no such increase was observed in patients administered CMA (Group I), indicating that CMA prevented the flare-up. Parameters of liver function, serum GOT and GPT levels, which were normal at the baseline, became abnormal in 30.0% and 35.3%, respectively, of patients in Group II. These figures were significantly higher than the corresponding figures of 6.3% and 12.5%, respectively, in Group I. When the degree of change in each of these parameters was analyzed, both GOT and GPT levels showed a significantly greater increase in Group II than in Group I. CONCLUSION: These results indicate that attention must be paid to changes in liver function during the administration of flutamide in patients with prostate cancer even if their baseline liver function is normal. It is also suggested that CMA may be better tolerated from the viewpoint of the drug effects on liver function.

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.

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.