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Objectives: The aim of the study was to update the results of a previous study published 10 years ago and compare the effect on hyperandrogenism of a newer progestin, dienogest (DNG), in a combined oral contraceptive (COC) formulation with ethinylestradiol (EE), with that of COCs containing the same dose of EE in combination with drospirenone (DRSP) and chlormadinone acetate (CMA). Methods: Sixty women with polycystic ovary syndrome (PCOS) aged between 16 and 35 and requiring antiandrogenic contraceptive treatment were randomised to one of three treatment groups: EE 30 µg/DRSP 3 mg, EE 30 µg/CMA 2 mg, EE 30 µg/DNG 2 mg. We evaluated the effects of the three COCs on sex hormone-binding globulin (SHBG) and biochemical markers of hyperandrogenism. Results: After 3 months of treatment, serum androgen concentrations were significantly improved in all treatment groups. Serum concentrations of SHBG were significantly increased with all COC treatments ( p  < 0.0001). Interestingly, DRSP had a greater effect (+218%; p  < 0.0001) on serum SHBG concentrations compared with DNG and CMA ( p  < 0.04 and p  < 0.002, respectively). Serum concentrations of total testosterone significantly decreased in all groups ( p  < 0.0001). DRSP had a significantly greater effect on total testosterone concentrations compared with DNG ( p  = 0.002) and CMA ( p  < 0.0001). Conclusion: Our study showed that DNG exerted an important stimulatory effect on SHBG concentrations, which was less than that of DRSP but greater than that of CMA. Similar results were also obtained for dehydroepiandrosterone sulphate and total testosterone.

Background: Polycystic ovary syndrome (PCOS) is a serious endocrinal disorder in women of reproductive age. Hormonal treatment with oral contraceptives, containing estrogen (ethinyl-estradiol, EE) with progestogen (drospirenone, DRSP) or (chlormadinone acetate, CMA), has improved symptoms and biomarkers of PCOS., Objective: The aim of the present meta-analysis is to compare the effects of EE/DRSP versus EE/CMA on the endocrinal features of women with PCOS., Data Sources: Several electronic databases were searched for combinations of the following relevant MeSH terms were used: (ethinyl-estradiol OR EE) AND (drospirenone OR DRSP) AND (chlormadinone acetate OR CMA) AND (polycystic ovary syndrome)., Methods: Records were screened for eligible studies and data were extracted to an online data extraction form. Outcomes of Ferryman-Gallwey score (FGS), body mass index, dehydroepiandrosterone sulfate (DHEAS), free androgen index, sex hormone-binding globulin, delta-4-androstenedione (A) and total testosterone levels (T) were pooled as weighted mean difference (WMD) and 95% confidence interval (CI) in a fixed effect meta-analysis model., Results: Three RCTs (EE/DRSP: n = 98 and EE/CMA: n = 87) were pooled in the analysis. The overall effect favoured EE/DRSP over EE/CMA in reducing (A) levels after three months (WMD -0.63; 95% CI [-0.94, -0.32], P < 0.001), FGS after six months (WMD -0.44; 95% CI [-0.99, -0.19], P = 0.0006), and total (T) after three months (WMD -0.12; 95% CI [-0.23, -0.01], P = 0.03)., Conclusions: EE/DRSP showed a more potent effect than EE/CMA in the reduction of FGS after six months, (A) levels and (T) levels after three months in patients with PCOS., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Chlormadinone acetate (CMA) is a derivative of the naturally secreted hormone progesterone and exhibits reliable contraceptive and non-contraceptive benefits. Although the marketed product of CMA as oral tablets under the trade name Belara® has been highly successful, there is still room for further improvements in oral bioavailability and a reduction in the clinical dose to decrease related adverse effects. In the current study, a CMA-based self-microemulsifying drug delivery system (SMEDDS) was developed using 32% ethyl oleate as an oil phase, 40% Tween-80 as a surfactant, and 12% Transcutol P combined with 16% PEG400 as a cosurfactant, resulting in spherical droplets with a z-average particle size of 38.92 nm and an average zeta potential of - 3.18 mv. The in vitro release rate of CMA from CMA-SMEDDS in different media (distilled water, HCl solution at pH 1.2, phosphate buffers at pH 4.5 and pH 6.8) was significantly faster than that from Belara® in the first 15 min. A pharmacokinetic study in rats showed that the C max and AUC of CMA-SMEDDS were significantly higher (P < 0.01) than those of Belara®, with a 1.98-fold increase in oral bioavailability. In comparison with Belara®, the developed CMA-SMEDDS showed promising release profiles both in vitro and in vivo, which could potentially be useful in enhancing oral bioavailability and reducing the clinical dose of CMA.

Introducción: La enfermedad renal crónica (ERC) se asocia con alteraciones menstruales, y el manejo del sangrado uterino suele ser complejo por las condiciones de este grupo de pacientes. El objetivo de este trabajo fue describir la respuesta clínica al tratamiento hormonal de las alteraciones menstruales de adolescentes con ERC., Métodos: Se presentan los datos de una serie de casos de pacientes adolescentes con ERC que cursaron con alteraciones menstruales y que recibieron tratamiento desde el año 2008 al 2012. Se identificaron las características del trastorno menstrual, del tratamiento hormonal recibido y de la respuesta al mismo. El análisis estadístico fue descriptivo., Resultados: Se estudiaron 11 pacientes de sexo femenino con edad promedio de 14.5 años, que se encontraban en prediálisis (n = 1), diálisis peritoneal (n = 7) y hemodiálisis (n = 3). Las pacientes presentaron hiperpolimenorrea asociada a la opsomenorrea (n = 3), en su mayoría clasificadas como hemorragia uterina anormal secundaria. El tratamiento, en general, fue con progestágenos de manera inicial (clormadinona con o sin medroxiprogesterona) o bien con anticonceptivos combinados. En la mayoría de las pacientes se obtuvo una respuesta favorable; sin embargo, hubo casos en los que fue necesario modificar la dosis y el tiempo de tratamiento., Conclusiones: La mayor parte de las adolescentes con ERC que han sido tratadas por hemorragia uterina anormal en nuestro estudio tuvieron una respuesta favorable al tratamiento hormonal., Background: Chronic kidney disease (CKD) is associated with menstrual abnormalities and management of uterine bleeding is often complex because of the conditions in this group of patients. The aim of this study was to describe the clinical response to hormonal treatment of menstrual alterations in adolescents with CKD., Methods: We present data of cases of adolescent patients with CKD who had undergone menstrual changes and received treatment during the period 2008 to 2012. The characteristics of the menstrual disorder, hormone treatment received, and response to treatment were evaluated. The statistical analysis aplicated to analyze the results was descriptive., Results: We studied 11 patients with a mean age of 14.5 years, who were in predialysis (n = 1), peritoneal dialysis (n = 7), hemodialysis (n = 3). Patients had hyperpolymenorrhea associated with opsomenorrhea (n = 3), mostly classified as secondary abnormal uterine bleeding. Treatment, in general, was with progestins initially (chlormadinone with or without medroxyprogesterone) or combined contraceptives. In the majority of the patients, a favorable response was obtained; however, there were cases where it was necessary to modify the dose and time of treatment., Conclusions: The majority of adolescents with CKD who have been treated for abnormal uterine bleeding in our study had a favorable response to hormonal treatment., (Copyright: © 2018 SecretarÍa de Salud.)

Aim: To observe the influence on metabolism and body composition of two oral contraceptives containing non-androgenic progestins in association with estradiol or ethinyl estradiol (EE)., Study Design: Women on hormonal contraception with estradiol valerate (E2V)/dienogest (DNG) in a quadriphasic regimen (n = 16) or 30 μg EE/2 mg chlormadinone acetate (CMA) (n = 16) in a monophasic regimen were evaluated at the third cycle for modifications in lipoproteins, apoproteins and homeostatic model assessment for insulin resistance (HOMA-IR), and at the sixth cycle for body composition and the markers of bone turnover osteocalcin and C-telopeptide X., Results: During E2V/DNG lipoprotein, apoproteins and HOMA-IR remained stable. During EE/CMA, total-cholesterol (p = 0.003), high-density lipoprotein (HDL)-cholesterol (p = 0.001), triglycerides (p = 0.003) Apoprotein-A1 (Apo-A1; p = 0.001) and Apo B (p = 0.04) increased, low-density lipoprotein/HDL (p = 0.039) decreased and total-cholesterol/HDL and Apoprotein-B/Apo-A1 ratio did not vary. HOMA-IR slightly increased from 1.33 ± 0.87 to 1.95 ± 0.88 (p = 0.005). There was a reduction of markers of bone metabolism in both groups with no modification of body composition., Conclusions: Administration of E2V/DNG does not influence lipid and glucose metabolism, while mixed effect are exerted by EE/CMA. Both preparations reduce bone metabolism without influencing short-term effect on body composition.

The aim of this study was to evaluate the efficacy of third-line combined androgen blockade (CAB) therapy for castration-resistant prostate cancer that relapsed after primary and second-line CAB. We retrospectively reviewed the medical records of 52 patients who received first-, second-, and third-line CAB therapy (medical or surgical castration, plus steroidal antiandrogen of chlormadinone acetate, or nonsteroidal antiandrogen of flutamide or bicalutamide). For cumulative analysis, we searched the PubMed database and identified a total of 50 cases published in English. Including our cases, this provided a total of 102 cases for analysis. In our study cohort, 11 cases (21.2%) achieved more than 50% reduction of serum prostate-specific antigen (PSA) on initiation of third-line CAB. We found that third-line CAB with nonsteroidal antiandrogen after second-line CAB with steroidal antiandrogen exhibited favorable results, with a positive response in six of 13 patients (46.2%). Cumulative analysis findings were comparable. Regarding the timing of third-line CAB administration, 15 patients had started at a PSA equal to or less than 4.0 ng/ml, and eight of them (53.3%) showed a positive response to treatment, compared to only three of 37 patients (8.1%) whose PSA at the initiation of third-line therapy was higher than 4.0 ng/ml (p<0.001). We conclude that third-line CAB with nonsteroidal antiandrogen would be particularly useful for patients whose cancer progressed after second-line CAB with steroidal antiandrogen. The timing of treatment seems to be important because the higher the PSA at the start of third-line therapy, the lower the PSA response rate.

Background: Skin and hair appearance is important to body image. Oily skin and oily, impaired hair quality, which can develop in women taking certain types of hormonal contraceptives, may cause psychosocial stress., Objectives: The aim of the current study was to investigate the effects of an oral monophasic contraceptive (0.03 mg ethinylestradiol/2 mg chlormadinone acetate) for 12 treatment cycles on the pathophysiology of oily skin and oily, impaired hair quality in healthy women., Methods: We assessed changes in hair and skin parameters at baseline, 12, 24 and 48 weeks, in 60 women aged 18-45 years. Psychological well-being was verified by two subject self-assessments (Hair quality, Hairdex)., Results: Data from 31 subjects showed that treatment significantly improved sebum excretion at capillitium and forehead, and the number of terminal hairs. Visual haptic scores revealed significant decreases in capillitium seborrhoea, hair condition/density, capillitium dandruff and irritation/redness. Subject self-assessment confirmed improvements in hair quality. Treatment was well tolerated., Conclusion: Chlormadinone acetate in hormonal contraception provides excellent cosmetic and dermatological benefits, which can improve psychosocial well-being., (© 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.)

The estrous cycle length in the white rhinoceros (Ceratotherium simum) is either 4 or 10 wk. The cause(s) for this variation as well as the poor fertility rate in captivity remains under debate in this species. Most captive adult white rhinoceros undergo long anovulatory periods without luteal activity which are considered a major reason for their low reproductive rate. In this study, the synthetic progestin chlormadinone acetate (CMA) was tested in combination with hCG or the GnRH analogue deslorelin for its efficiency to induce ovulation in fourteen females without luteal activity and in three, regular cycling females. HCG (N = 12), injectable GnRH analogue (N = 8) and GnRH analogue implants (N = 15) were given to induce ovulation after CMA treatment. Treatment success was determined using both transrectal ultrasonography and progesterone metabolite EIA analysis. A preovulatory sized follicle (3.5 ± 0.1 cm) or a corpus luteum (5.1 ± 0.7) was present on the ovary one day after induction in 93.1% of the treatments. Despite this high rate of ovarian response, ovulation rate differed between the study groups. The ovulation rate for hCG, injectable GnRH analogue and GnRH analogue implants was 66.7%, 62.5% and 93.3%, respectively. Ovulation rate in cyclic females treated with GnRH implants was 100% (6/6) compared with 89% (8/9) in females without luteal activity receiving the same treatment. The length of the estrous cycle when induced with hCG was 4 wk (85.7%). The estrous cycle when induced with GnRH analogue was predominantly 10 wk long. Two females without luteal activity treated with GnRH became pregnant. In conclusion, CMA in combination with GnRH analogue implants was highly effective to induce ovulation in white rhinoceroses and thus can contribute to efforts aimed at increasing natural mating and reproductive rates in the captive white rhinoceros population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Primary hormonal therapy has been mostly used for patients with advanced prostate cancer, as international guidelines do not recommend its use for patients at earlier disease stages. However, there seems to be a discrepancy between the guideline recommendations and clinical practice on the use of primary androgen deprivation therapy for localized prostate cancer in Japan. Therefore, we retrospectively analyzed a single-institution experience in primary combined androgen blockade (CAB) for localized prostate cancer., Patients and Methods: The study included 187 patients with T1c-T3a prostate cancer unsuitable for local definitive treatment and treated with primary CAB. Clinical outcomes, predictive factors of PSA relapse and adverse events were investigated., Results: The progression-free, disease-specific, and overall survival rates of all patients at 5 years were 63.0, 99.4 and 95.9%, respectively. Of the several parameters isolated as predictors of prostate-specific antigen (PSA) progression, nadir PSA level and the percentage of positive biopsy cores (%PBC) remained as independent prognostic factors on multivariate analysis. Toxicities were mild to moderate and well tolerated., Conclusions: Primary CAB treatment brought initial disease control without relapse in the majority of our selected cases. The %PBC may help predict time to relapse in the pretreatment setting. The results implicate that CAB can be an option as a primary treatment for clinically localized prostate cancer unsuitable for local definitive treatment. To confirm the exact efficacy of primary CAB, these findings should be reviewed in a large cohort of patients with long-term follow-up from various viewpoints, including disease control, toxicities, quality-of-life and medical cost.

Background: The study was conducted to assess the contraceptive efficacy, cycle events, dysmenorrhea symptoms and skin complaints of a combined oral contraceptive containing 2 mg chlormadinone acetate/0.03 mg ethinylestradiol (CMA/EE) (Belara®, Grünenthal GmbH, Aachen, Germany) in adolescent and adult women using a conventional- or extended-cycle regimen., Study Design: Data were pooled from six noninterventional trials with CMA/EE intake over 4-12 cycles., Results: The data pool contained 62,218 women (345,964 cycles), of whom 60,508 were analyzed (325,937.5 cycles), including 46,335 adults, 13,478 adolescents and 695 age unknown; 1710 retrospective documented patients were excluded from analysis. A total of 85 women became pregnant (including women missing pills) on the conventional-cycle regimen (21+7), giving a practical Pearl index of 0.34 [95% confidence interval (CI) 0.27-0.42]. Within this group (n=85), there were 19 pregnancies associated with regular pill intake, which represent a theoretical Pearl index of 0.08 (95% CI 0.05-0.12) per 100 women-years. Overall, cycle stability, bleeding profile, dysmenorrhea and the incidence of seborrhea/acne improved with CMA/EE, and there was no clinically relevant change in body weight or body mass index. Six venous thromboembolic events were reported, equating to an incidence of 2.4 per 10,000 women-years., Conclusions: Chlormadinone acetate/ethinylestradiol is effective and well tolerated in adolescent and adult women., (Copyright © 2011. Published by Elsevier Inc.)

Background: Low-dose oral contraceptives can still cause thromboembolic disorders with serious neurologic or ocular disabilities., Patient: A 22-year-old woman having used oral contraceptives for several months noticed sudden painless visual loss in her left eye. One tablet of her contraceptive contained ethinylestradiol (0.03 mg) and chlormadinonacetate (2 mg)., Result: Because of the lower left eye visual field defect, the patient could only read with her right eye. She presented complete left inferior hemianopia, indicating a hemicentral retinal artery obstruction. Visual acuity in both eyes was 20 / 20. The left fundus revealed a distinct retinal edema in the area superior to the optic disc and macula due to vascular disturbances of the superior temporal superior and superior nasal retinal arteries. The right eye was normal. Fluorescein angiography revealed recanalized arteries in the superior retinal area with conspiciously early dye filling as a paradoxical sign. Doppler sonography of the neck and orbital arteries and transesophageal echocardiography (TEE) findings were inconspicious. However, blood examination revealed an elevated thrombin-antithrombin complex and reduced free protein S., Conclusion: Coagulopathy can be a side effect of oral contraceptives. Even nowadays, women taking contraceptives risk the danger of vascular occlusions especially if the women suffers from arterial hypertension, diabetes mellitus, have a coagulation anomaly, or if she is a chronic smoker. Before treatment with oral contraceptives commences, a thorough medical examination is necessary. If the family history reveals prominent cardiovascular risk factors, testing for thrombophilia is recommended. Even nowadays, patients should be warned of the risk of visual field defects as a potential side-effect associated with oral contraceptives., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Systemic lupus erythematosus (SLE) affects women of child-bearing age. Combined oral contraceptives can worsen the course and increase the risk of thrombosis. The objectives of this study were to provide an alternative contraception and thus evaluate the gynecological tolerability of pregnane progestins (PPs) in SLE patients. Systemic lupus erythematosus disease activity and vascular tolerance were also reported., Study Design: We used two PP with antigonadotropic potencies, chlormadinone acetate (CMA, 10 mg/day) and cyproterone acetate (CPA, 50 mg/day), administered orally for contraception in 187 SLE patients observed for 46±34.6 months (mean±S.E.), i.e., 6854 women-months., Results: The gynecological tolerability was satisfactory: breakthrough bleeding was reported in 17.7% patients using CPA and 12.6% patients using CMA. No pregnancy was observed in the women followed in this cohort study. One deep vein thrombosis, one myocardial infarction, and one tibial posterior arterial occlusion were observed, giving an incidence for venous thromboembolism of 1.39/year×1000 women (95% CI 0-4.12) and for macroarterial disease an incidence of 2.79/year×1000 women (95% CI 0-6.65). Disease activity was less than before progestins., Conclusions: Pregnane progestin contraception is effective and well tolerated, thus providing SLE patients an excellent contraceptive alternative to the currently used methods., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: This study was conducted to examine whether small doses of ethinylestradiol (EE, 0.02 mg) and chlormadinone acetate (CMA, 2 mg) administered in a novel 24/4-day regimen during six cycles would suffice to suppress proliferation and to cause secretory changes in the endometrium., Study Design: This Phase II, randomized (two assessment groups), single-center, open, uncontrolled, multiple-dosing study treated 59 female subjects. The subjects underwent three endometrial biopsies: one pretreatment, one during medication (either at Cycle 3 or Cycle 6) and one during the first post-treatment cycle., Results: The study revealed that 0.02 mg EE/2 mg CMA effectively transformed the endometrium from a proliferative state into a secretory or inactive state after three (90% of subjects) and six (76% of subjects) medication cycles. The mean endometrial thickness decreased markedly from 10.2 (SD±3.0) mm (pretreatment) to an unfavorable level for the nidation of a blastocyst [5.3 (SD±2.1) and 4.1 (SD±2.2) mm in Medication Cycles 3 and 6, respectively]. Correspondingly, estradiol and progesterone levels decreased during treatment. In the post-treatment cycle, endometrial biopsy and ultrasound evaluation as well as sex hormone levels suggested a quick return to fertility. There were no signs of hyperplasia, endometrial polyps, neoplasia or other detrimental histopathological changes at any time during the trial. Treatment-related adverse events (AEs) were reported by 22 (37%) of 59 subjects and were reported most commonly in Cycle 1, decreasing continuously thereafter. No AEs led to discontinuation of the trial medication and there were no serious AEs., Conclusions: The 24/4-day regimen of 0.02 mg EE/2 mg CMA provided effective and reversible endometrial effects with secretory transformation or suppression without inducing pathological changes., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To describe the suppression of ovarian function with 0.02 mg ethinyl E(2)-2 mg chlormadinone acetate administered in a 24/4-day intake regimen in healthy women., Design: Open, uncontrolled, multiple dosing, phase II trial., Setting: Single clinic., Patient(s): Forty women treated., Intervention(s): Treatment for up to three cycles with 0.02 mg ethinyl E(2)-2 mg chlormadinone acetate given in a 24/4-day regimen., Main Outcome Measure(s): Assessments of ovarian function classified by the Hoogland and Skouby score, thickness of endometrium, cervical reaction, and sex hormone levels, as well as overall tolerability., Result(s): No ovulation was observed in the per protocol set (N=36), and one in the full analysis set (N=38) after vomiting and diarrhea. Absence of ovarian activity, residual ovarian activity, and formation of a luteinized unruptured follicle were observed in 75.0%, 15.9%, and 1.1% of medication cycles, respectively. Endometrial thickness was suppressed to 4 to 5 mm compared with 10 to 12 mm without medication. Cervical reaction was negative. Hormone levels were lower with medication than without, and the medication was well tolerated. Treatment-related adverse events were typical of those associated with hormonal contraceptive use., Conclusion(s): Follicular development, cervical reaction, and endometrial thickness were suppressed profoundly after 0.02 mg ethinyl E(2)-2 mg chlormadinone acetate administration in a 24/4-day regimen, resulting in inhibition of ovulation and unfavorable conditions for fertilization, implantation, and thus pregnancy., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Chlormadinone acetate (CMA) is a progestin compound similar to progesterone, with antiandrogenic properties. In healthy eumenorrheic women, it was demonstrated that the monophasic estroprogestin formulation containing CMA (2 mg) plus ethinyl estradiol (EE) (30 mcg) (EE30+CMA) is efficacious both in reducing hyperandrogenic symptoms, fat mass and in improving lipoprotein panel, without changes in insulin-glucose metabolism. These metabolic properties are important for women affected by polycystic ovary syndrome (PCOS) in whom there is a predisposition to insulin resistance., Study Design: We studied whether in young nonobese women with PCOS (15 subjects, EE30+CMA-PCOS group) a six-cycle treatment with EE30+CMA can reduce androgen levels, androgen bioavailability and the score of hirsutism and acne, and modify glucose-insulin metabolism evaluated by the oral glucose tolerance test and the body composition evaluated by bio-impedenziometry. These parameters were evaluated before (first visit) and during the sixth cycle of EE30+CMA (second visit). All the results were compared with those of a matched-age-group of nonobese PCOS women (15 subjects, no OC-PCOS group) evaluated before (first visit) and after six menstrual cycles in which they did not use any drug or oral contraceptive (second visit)., Results: In the EE30+CMA-PCOS group women, androgen levels and bioavailability, hirsutism and acne score were significantly lower at the second than at the first visit, whereas they did not change in no OC-PCOS group. At the second visit, in both groups, glucose-insulin metabolism and body composition parameters were not affected., Conclusions: A six-cycle treatment with EE30+CMA is efficacious in nonobese PCOS women to improve hyperandrogenic symptoms, without negative interferences both on body composition and on insulin-glucose metabolism., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: This study was conducted to assess the long-term efficacy and safety of a low-dose monophasic combined oral contraceptive (COC) containing 0.02 mg ethinylestradiol (EE) and 2 mg chlormadinone acetate (CMA) in a novel regimen administered daily for 24 days followed by a 4-day placebo interval., Study Design: In this multicenter, uncontrolled, Phase III trial, 1665 subjects took the COC 0.02 mg EE/2 mg CMA for up to 21 cycles. The overall Pearl Index was the primary end point; cycle control, safety, effect on acne and seborrhea, and changes in body weight and libido were secondary end points., Results: Contraceptive efficacy was analyzed for 1653 subjects completing 21,495 cycles. Six pregnancies occurred during trial duration with one attributable to method failure. The overall Pearl Index for the first year of use was 0.33 (95% confidence interval, 0.09-0.85). The mean number of bleeding/spotting days during six 90-day reference periods (RPs) decreased from 17.0 (RP 1) to 11.7 (RP 6), and the number of bleeding episodes per RP decreased from 3.8 (RP 1) to 2.7 (RP 6). Among subjects who presented with acne at the baseline visit, a decrease of papules/pustules and comedones was observed during the course of the trial. The most common "at least possibly related" adverse events were headache, breast discomfort and nausea. The tolerability and well-being was reported as being excellent or good in the majority of trial subjects (84.6% and 80.2%, respectively)., Conclusions: The low-dose COC 0.02 mg EE/2 mg CMA administered daily for 24 days followed by a 4-day placebo interval provides high contraceptive efficacy combined with an adequate cycle control and safety profile, beneficial effects on acne, and is well tolerated.

Objectives: To investigate hot flashes and quality of life during combined androgen blockade (CAB) therapy using steroidal or nonsteroidal antiandrogens., Methods: A total of 151 patients with prostate cancer, who were enrolled into this study from May 2001 to June 2003, were randomized to receive CAB therapy using a luteinizing hormone-releasing hormone agonist (leuprorelin) combined with a steroidal antiandrogen (chlormadinone) or a nonsteroidal antiandrogen (bicalutamide). The incidence of, frequency of, and distress due to hot flashes were evaluated with a self-administered questionnaire during a 2-year period. The general and disease-specific quality-of-life outcomes were also measured using the Functional Assessment of Cancer Therapy-Prostate questionnaire., Results: Data were available for analysis from 124 patients. Although the incidence of hot flashes largely tended to be greater in the bicalutamide group than in the chlormadinone group, no significant difference was noted in the cumulative incidence of hot flashes at 2 years. The median frequency of hot flashes daily was 1.3 and 2.2 for warmth/flushing (P = .16) and 1.0 and 3.6 for sweating (P = .021) in the chlormadinone and bicalutamide groups, respectively. Patients in the chlormadinone group were significantly less likely to be distressed by warmth/flushing (odds ratio 0.47, P < .001) and sweating (odds ratio 0.61, P = .01) than were those in the bicalutamide group. The Functional Assessment of Cancer Therapy-Prostate scores over time showed no intergroup differences., Conclusions: Our results suggest that CAB using a steroidal antiandrogen such as chlormadinone might induce fewer and less-distressing hot flashes than CAB with bicalutamide.

The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol (CAS 57-63-6) and chlormadinone acetate (CAS 302-22-7) (Bellissima as test and the respective preparation from the originator as reference) were investigated in 20 healthy female volunteers after oral single-dose administration. The study was performed according to a single-center, randomised, single-dose, 2-way cross-over design with a wash-out phase of 28 days. Blood samples for pharmacokinetic profiling were taken up to 168 h post-dose, and ethinylestradiol and chlormadinone acetate plasma concentrations were determined with a validated LC-MS/MS method. The observed mean maximum plasma concentrations (Cmax) of ethinylestradiol were 124.96 pg/ml (test) and 129.12 pg/ml (reference). In the case of chlormadinone acetate, Cmax averaged 6.9566 ng/ml (test) and 6.6663 ng/m (reference). The geometric means of area under the plasma concentration-time curve (AUC(0-infinity)) of ethinylestradiol were 1292.35 pg/ml x h (test) and 1380.49 pg/ml x h (reference). For chlormadinone acetate, geometric means of AUC(0-infinity) were 53.322 ng/ml x h (test) and 58.111 ng/ml x h (reference). The median of tmax of ethinylestradiol was 1.5 h for both test and reference and the median of tmax of chlormadinone acetate 1.0 h (test) and 1.5 h (reference). Plasma elimination half-lives (t1/2) of ethinylestradiol were 14.96 h (test) and 15.41 h (reference) and of chlormadinone acetate 56.63 h (test) and 56.17 h (reference), respectively. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA). The point estimator and the 90% confidence intervals for the AUC(0-infinity) ratio (test/reference: 93.72% [86.62%-101.39%]) indicate high similarity of both formulations with respect to the extent of ethinylestradiol exposure. A high degree of similarity was also observed for Cmax of ethinylestradiol, as the point estimator and the 90% confidence interval for the Cmax ratio are 96.18% (90.82%-101.86%). Regarding the AUC(0-infinity) ratio of chlormadinone acetate, the point estimator is 91.60% and the 90% confidence interval 84.08%-99.79%. Furthermore, exchangeability of both formulations is also suggested by the point estimator and 90% confidence of Cmax of this active agent (104.72% [95.76%-114.53%]). Bioequivalence between test and reference formulation was demonstrated since for both ethinylestradiol and chlormadinone acetate all 90% confidence intervals of AUC(0-infinity) and Cmax fall into the generally accepted range of 80%-125%.

Aim/methods: In vitro binding tests to human receptors and in vivo functional activities in animals were used to compare the effects of the progestin chlormadinone acetate (CMA) and its 3alpha- and 3beta-hydroxy metabolites (3alpha-OH-CMA and 3beta-OH-CMA) on progesterone, androgen and glucocorticoid receptors., Results: CMA, 3alpha-OH-CMA, 3beta-OH-CMA and the reference progestin R5020 bound to human progesterone receptor with Ki values of 2.5 nm, 13 nm, 6.0 nm and 4.3 nm, respectively. Binding affinities to the human androgen receptor were characterized by Ki values of 3.8 nM for CMA, 83 nM for 3alpha-OH-CMA, 20 nM for 3beta-OH-CMA and 2.9 nM for the reference androgen methyltrienolone. The Ki values for binding to the human glucocorticoid receptor were 16 nM for CMA, 69 nM for 3alpha-OH-CMA, 21 nM for 3beta-OH-CMA and 1.2 nM for the glucocorticoid dexamethasone. In the rabbit endometrial proliferation test CMA, 3alpha-OH-CMA and 3beta-OH-CMA (5 and 45 microg/kg p.o. for 5 days) had similar progestomimetic activities. CMA, 3alpha-OH-CMA and, to a lesser extent, 3beta-OH-CMA (4.64 and 21.5 mg/kg p.o. for 7 days) inhibited testosterone-stimulated growth of prostate and seminal vesicles in castrated rats showing antiandrogenic activities. Glucocorticoid properties were demonstrated for CMA and 3alpha-OH-CMA (21.5 and 100 mg/kg p.o. for 6 days) but not for 3beta-OH-CMA as reduction in thymus and adrenal gland weights in immature rats., Conclusion: Binding assays at human receptors showed similarly high affinities of CMA with the progesterone and androgen receptors and a 5 times lower affinity with the glucocorticoid receptor. At all receptor types, CMA had the highest, 3alpha-OH-CMA the lowest and 3beta-OH-CMA an intermediate affinity. Animal studies revealed progestomimetic and antiandrogenic activities of CMA, 3alpha-OH-CMA and 3beta-OH-CMA and glucocorticoid activities of CMA and 3alpha-OH-CMA.

Hyperandrogenic manifestation in women, such as seborrhea, acne and increased hair growth are common reasons of psychological distress. Skin appearance is very important for young women. This study evaluated the hormonal and skin effects of two estroprogestins (EPs) containing ethinyl-estradiol (EE) 30 microg associated with drospirenone (DRSP) 3 mg or chlormadinone acetate (CMA) 2 mg, respectively. Fifty-five women with signs and symptoms of hyperandrogenism (seborrhea, acne and increased hair growth) were enrolled in the study; randomly, 30 women were treated with EE 30 microg + DRSP 3 mg and 25 with EE 30 microg + CMA 2 mg. Follicle-stimulating hormone (FSH), luteinising hormone (LH), 17-hydroxyprogesterone (17OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG) and free androgen index (T x 100/SHBG, FAI) were assessed at baseline, and after 3 and 6 months of treatment with EPs. Effects on seborrhea, acne and increased hair growth (as Ferriman-Gallwey score) were also evaluated at the same time points. Finally, skin hydration, transepidermal water loss (TEWL) and skin homogeneity were studied with non-invasive technique during the study. Treatment for 6 months with both EPs decreased significantly the circulating androgen levels (A, T, DHEAS) and FAI, and increased SHBG levels; also skin pattern was improved. EP containing EE and DRSP was better than EP containing EE and CMA as for skin changes, as seborrhea, acne, increased hair, hydration, homogeneity and overall quality of the skin; moreover, hormonal changes (as FAI) under therapy were more pronounced with EE/DRSP than EE/CMA. These effects may be considered in EP choice and could be important in improving patient's compliance and quality of life in hyperandrogenic women.

An 80-year-old male visited the hospital as an outpatient with a head injury sustained in a traffic accident. Brain computed tomography incidentally revealed a left frontal lobe tumor measuring 5 cm in a diameter. The patient had a history of taking chlormadinone acetate (a progesterone agonist) prescribed several years previously as treatment for benign prostatic hypertrophy. The tumor was seen as an isointense lesion on T(1)-weighted magnetic resonance (MR) images with enhancement by gadolinium, and as a heterogeneously hyperintense mass on T(2)-weighted MR images. The tentative diagnosis was left frontal meningioma attached to the sphenoid ridge or sphenoid plane. The patient was managed conservatively because of his advanced age and no symptoms or progression were observed during a 9-month follow-up period. The medication for benign prostatic hypertrophy was changed from chlormadinone acetate to naftopidil (an alpha-2-blocker) about 9 months after his first presentation. The patient presented again 2 years later complaining of dizziness. Computed tomography and MR imaging performed at this time revealed remarkable regression of the tumor. The signal intensity change with regression of the tumor on T(2)-weighted images was observed as a hypointense lesion. Thus, we wish to emphasize that treatment of meningiomas, especially those diagnosed incidentally, must be based on a thorough consideration of any history of hormonal therapy with prostate disease.

Background: This open-label, noncontrolled study assessed the long-term efficacy and tolerability of the monophasic combined low-dose oral contraceptive (OC) ethinyl estradiol (EE) 30 mcg+chlormadinone acetate (CMA) 2 mg (Belara)., Study Design: In total, 781 women who had already taken EE 30 mcg+CMA 2 mg for 24 cycles in a previous Phase III study were assessed for up to 45 cycles., Results: Over 23,033 cycles, the Pearl Index was 0.16 (95% confidence interval, 0.04-0.42). Approximately 86% of women had regular withdrawal bleeding in each cycle, while incidence of intracyclic bleedings (1.6-6.4%) and proportion of women with amenorrhea (4%) were low. The incidence of acne decreased from 13.8% to 5.7%, while rates of hirsutism, alopecia and seborrhea remained low (< or =4%) throughout this study. The most frequent adverse events were consistent with OC treatment, and no unexpected events occurred. No changes in mean blood pressure and pulse rate were observed during the study, and there were no clinically relevant changes in liver or hematological parameters, hemostasis or carbohydrate metabolism. The incidence of pathological findings in gynecological examination was low and decreased over time., Conclusion: EE 30 mcg+CMA 2 mg was an effective and well-tolerated OC, with beneficial effects on cycle stability, intracyclic bleeding, amenorrhea and signs of androgenization that were maintained during long-term treatment for up to 5 years. There was no evidence of an increased risk of thromboembolic events, atherogenic disease or cervical cancer, suggesting that 30 EE mcg+CMA 2 mg is highly suitable for long-term use.

Objectives: To evaluate the efficacy of oral progestogen, chlormadinone acetate, and intramuscular (IM) progesterone for luteal support in patients, undergoing assisted reproductive technology (ART) treatment, who were treated with a gonadotropin-releasing hormone agonist (GnRHa)., Methods: This was a prospective randomized study of 40 patients with normal and high response (serum estradiol > 2,000 pg/ml) in GnRHa down-regulation. Patients were randomized to receive either oral chlormadinone acetate or IM progesterone. The outcomes of ART treatment, including pregnancy and embryo implantation rates, were analyzed., Results: There were no significant differences in the clinical pregnancy rates (25 vs. 20%) and in the implantation rates (12.7 vs. 9.1%) of patients who received IM progesterone and oral chlormadinone acetate. Endometrial thickness was also comparable between oral chlormadinone acetate and IM progesterone., Conclusion: Oral progestogen, chlormadinone acetate showed a comparable pregnancy rate and live birth rate with IM progesterone as luteal support for the high responders. The optimal methods for luteal support may be dependent on responses to stimulation with gonadotropin, although it is not concluded that oral chlormadinone acetate is recommended as an option for luteal support in high responders.

Objective: To describe the modulation of ovarian function during three medication cycles with 0.03 mg ethinyl oestradiol (EE) and 2 mg chlormadinone acetate (CMA), leading to inhibition of conception in healthy women., Methods: Phase II, single-centre, open, non-controlled trial. The main outcome measure was inhibition of ovarian activity, assessed by frequent monitoring of the presence, size and persistence of follicle-like structures using ultrasonography. Secondary parameters included: cervical reaction score (CRS-probability of fertilization), endometrial thickness (probability of nidation), and serum levels of the sex hormones oestradiol, progesterone, luteinizing hormone and follicle stimulating hormone. Safety was primarily assessed by monitoring the occurrence of adverse events., Results: Thirty-three subjects were eligible for the trial and were included in the efficacy assessment (per protocol analysis, PPA). All subjects ovulated during the pretreatment cycle, but none during the three medication cycles. Follicular growth was profoundly suppressed during the medication phase, with residual ovarian activity occurring in only 12/83 (14.5%) treatment cycles. The CRS was negative during each medication cycle and endometrial thickness was suppressed on each medication day, with median values of 4.0-6.0 mm. EE/ CMA was well tolerated, with few adverse events reported; most were typically cycle-related and included headache, breast discomfort, nausea and vomiting., Conclusion: During the administration of EE/CMA follicular development, cervical reaction and endometrial thickness are profoundly suppressed, resulting in unfavourable conditions for fertilization, implantation and, thus, pregnancy.

Background and Objective: Many women of reproductive age experience depressive mood symptoms such as sudden mood swings, irritability, nervousness, excitability and anxiety. Although not defined as a disease, these disturbing mental symptoms are associated with a considerable decrease in quality of life. Molecular pharmacology research over the last 20 years has shown that endogenous steroid hormones may interact with the CNS. Some of these hormones, i.e. the sex hormone progesterone and its 3alpha-reduced metabolites allopregnanolone (3alpha,5alpha-tetrahydroprogesterone) and epipregnanolone (3alpha,5beta-tetrahydroprogesterone, eltanolone), influence mood-balancing and anxiolytic effects via the gamma-aminobutyric acid receptor A (GABA(A)), a major inhibiting receptor of the CNS. Activation of GABA(A) receptor results in mood balancing, anxiolytic, antiepileptic and sedative actions. When oral contraception is considered, it should be taken into account that the various synthetic progestogens used may differ in their influence on mental state. For instance, there is strong clinical evidence of mood-balancing effects for the progesterone derivative chlormadinone acetate (CMA). The aim of these studies was to describe the clinical effects of CMA in combination with ethinylestradiol on depressive mood symptoms., Methods: Data from four prospective, non-interventional observational studies involving nearly 50 000 women were analysed. The studies documented use of four, six and 12 treatment cycles of the 28-day conventional regimen, as well as providing data on extended cycle regimens. The women in these studies were prescribed CMA 2 mg and ethinylestradiol (EE) 0.03 mg according to gynaecologists' usual practice., Results: Clinical data from the studies confirmed that intake of CMA 2 mg and EE 0.03 mg promotes emotional well-being and reduces mood swings. Improvement in depressive mood was documented after four, six and 12 treatment cycles of the conventional intake regimen as well as with an extended-cycle regimen of CMA/EE., Conclusion: CMA 2 mg combined with EE 0.3 mg improves symptoms of depressive mood. The high structural congruence between the endogenous GABA(A) modulator epipregnanolone and the CMA metabolite M-V suggests a direct GABAergic, mood stabilizing function of CMA. We propose a theoretical concept - the CMA-GABA(A) model - that could explain the positive psychotropic effect of CMA.

Stage C prostate cancer, where the tumour has extended beyond the capsule of the prostate, is typically a high-risk disease. According to the National Cancer Institute Physician Data Query the treatments of choice for stage C disease comprise external beam radiation therapy (with or without the addition of adjuvant hormone therapy), androgen deprivation by either surgery or hormone therapy, radical prostatectomy, or careful observation. From 2001, the Japanese Urological Association initiated computer-based registration of all patients with prostate cancer in Japan. Data show that overall, 57% of all patients and 46% of those with T1c to T3 disease had primary androgen deprivation therapy (PADT). Similarly, the Japanese Prostate Cancer Group undertook a large-scale epidemiological surveillance study in Japan and found that the most commonly used hormone therapy is PADT, regardless of disease stage. To date, two randomized, controlled trials of the effect of PADT on stage C prostate cancer in elderly (> or =75 years old) patients have been undertaken in Japan. The results showed that patients with locally advanced prostate cancer treated with PADT are likely to have a life-expectancy similar to that of the normal population. In one study, combined androgen blockade (CAB) with leuprorelin plus chlormadinone appeared to prolong time to disease progression when compared with leuprorelin monotherapy, but there was no difference in survival between these treatment groups. In a second study CAB with an luteinizing hormone-releasing hormone (LHRH) agonist plus bicalutamide was found to prolong time to progression when compared with LHRH agonist monotherapy, but survival results for these regimens are still awaited.

Objective: To evaluate the efficacy of one intraprostatic injection with sustained-release chlormadinone acetate (CMA-SR) in rats., Materials and Methods: CMA, a steroidal antiandrogen, was enclosed in microcapsules for sustained-release (CMA-SR). Forty-eight rats were divided into group A (intraprostatic CMA-SR 8 mg/kg, one injection), group B (as A but with 25 mg/kg), group C (intraprostatic, vehicle only) and group D (subcutaneous, s.c., CMA 10 mg/kg once daily for 4 weeks). Prostate weight, body weight and plasma testosterone levels were measured for up to 4 weeks., Results: After a s.c. injection with CMA-SR, residual CMA at the s.c. injection site decreased with time. The injected prostate lobe weighed significantly (P < 0.05) less than the contralateral lobe in groups A and B, and significantly (P < 0.05) less in groups A and B than in group C. Both prostate lobes in group D were significantly (P < 0.05) smaller than in group C (P < 0.05). Plasma testosterone levels were significantly lower in group D than in group C (P < 0.05)., Conclusions: The sustained release of CMA after one intraprostatic injection persistently decreased the weight of the target prostate. This new concept of antiandrogen therapy might therefore be effective in man, with fewer systemic adverse reactions.

Background: Anxiety and depression commonly occur in premenstrual dysphoric disorder (PMDD). The PMDD symptomatology disappears once the menstrual cycle reinitiates, resembling a withdrawal syndrome., Methods: The present study is a pilot, controlled, double-blind study exploring the effectiveness of a premenstrual 5-day gradual reduction regimen of chlormadinone acetate on PMDD. Volunteers received an initial dose of 10 mg (five 2-mg tablets) on the 24(th) day of the menstrual cycle and one-fifth of the dose less (one tablet) each day until a dose of 2 mg (one 2-mg tablet) was reached on the 28(th) day of the menstrual cycle. The control group received placebo with a similar regimen., Results: The 5-day gradual reduction regimen of chlormadinone significantly improved (F(3.76) = 3.29, p <0.02) the daily symptoms report (DSR) scores by the third month of treatment. The resulting relative risk was 4.09 (confidence interval: 1.15-14.57, p <0.005, 95% CI). Compared to placebo, chlormadinone clinically and statistically reduced the severity of depression, anxiety, food cravings, mood swings and cramps. A statistical reduction of symptoms such as poor coordination, irritability, feeling out of control, hopelessness, decreased interest and headache was detected but was not clinically relevant. No changes occurred in concentration difficulties, tiredness, insomnia, swelling, breast tenderness and aches. As side effects, 30% of the volunteers showed changes in the length of the menstrual cycle, and 15% experienced dyspepsia., Conclusions: A 5-day gradual reduction regimen of chlormadinone improves some of the discomforting ailments associated with PMDD, namely, depression and anxiety.

Background: Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z))., Materials and Methods: Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography-mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose., Results: Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of approximately 400-500 pg/mL for CMA and 20-40 pg/mL for EE. Mass balance factors were 1.2-1.4 for CMA and 1.6-1.7 for EE, and accumulation factors were 1.7-2 for CMA and 1.7-1.8 for EE. Mean t(1/2,z) of CMA was approximately 25 h after single dosing and 36-39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3+/-6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively., Conclusions: The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t(1/2,z) of CMA was 36-39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature.

Background: Antiandrogens used to treat benign prostatic hyperplasia (BPH) may affect the diagnosis of prostate cancer by decreasing serum prostate-specific antigen (PSA) values. We conducted a retrospective survey of BPH patients treated with chlormadinone acetate (CMA) and analysed the effect of CMA on their PSA values., Methods: A chart-based, retrospective, multi-institutional survey of clinically diagnosed patients with BPH who had been treated with CMA (Prostal; 50 mg/day) was conducted. The patients were divided into three groups according to their baseline PSA values: <4 ng/mL, Group I; >or=4 ng/mL and <10 ng/mL, Group II; and >or=10 ng/mL, Group III. The changes in the PSA values from baseline after 16, 26, and 52 weeks of CMA therapy were predicted using a nonlinear regression model analysis., Results: Data from 192 of the 303 enrolled patients were analysed. The predicted percent changes from baseline among all patients after 16, 26, and 52 weeks of treatment were -49.6%, -49.8%, and -49.9%, respectively. The corresponding values were -42.4%, -43.7% and -43.8% in Group I; -57.4%, -58.4% and -58.5% in Group II; and -50.6%, -50.6% and -50.6% in Group III, respectively., Conclusion: The PSA values reached a nadir, approximately -50% of the baseline, after 16 weeks of CMA administration and remained at the same level thereafter. When CMA is used to treat BPH patients, the possibility of abnormal increases in PSA associated with prostate cancer must be considered; if prostate cancer is suspected, prompt testing, including a biopsy, should be performed.

Pure red cell aplasia (PRCA) is characterized by anemia with reticulocytopenia but with normal leukocyte and platelet counts, and a bone marrow with a selective absence of erythroid precursor cells. Drug-induced PRCA is a rare secondary form of PRCA, and is usually acute and fully reversible by the withdrawal of the causative drugs. We report a rare case of PRCA in a prostate cancer patient treated with combined androgen blockade (CAB) consisted of leuprolide acetate as a luteinizing hormone-releasing hormone agonist and chlormadinone acetate as an antiandrogen. This case demonstrated that these drugs could be a cause of PRCA, and suggests that regular close monitoring for anemia is needed in prostate cancer patients treated with these drugs.

Purpose: To clarify the optimal duration and methods for adjuvant endocrine therapy after external beam radiation therapy (EBRT) in patients with locally advanced prostate cancer., Materials and Methods: Between 2001 and 2003, 215 patients with locally advanced prostate cancer were enrolled in the study. Patients were registered as primary candidates of the study and were treated with 6 months of LHRH agonist, with short-term of antiandrogen treatment for flare-up prevention. Patients with PSA levels below 10 ng/ml after the 6-month endocrine treatment were randomly divided into two arms. Then, a total dose of 72 Gy was given to the prostate. After 14 months of the protocol treatment, patients were treated with continuous androgen ablation (arm 1) or intermittent androgen ablation (arm 2)., Results: A total of 188 cases (87%) remained in the protocol. The median PSA level at entry was 25.3 ng/ml. The Gleason score was 2-6 in 32 cases (16%), 7 in 94 cases (48%), and 8-10 in 68 cases (35%). The median PSA level showed a remarkable decrease to 1.1, 0.2, and 0.1 ng/ml, after 6, 8, and 14 months of the protocol treatment, respectively. Of the 157 cases treated with EBRT, 153 cases (97.5%) had no biochemical failure in the mean follow-up of 17.3 months., Conclusions: The present study may reveal the possibilities of intermittent endocrine therapy after EBRT. However, the follow-up interval is short and little can be said about the results observed so far, exception of acute tolerance and patient acceptance of the protocol., (Copyright (c) 2004 Wiley-Liss, Inc.)

Background: Ocular function is modified with hormone therapy; however, reports in literature are highly controversial., Objective: To analyze how hormone therapy modifies intraocular pressure and the number of tears shed by Mexican women., Patients and Methods: Eighteen postmenopausal women were studied and randomly divided into two groups, according to the treatment they received: group 1, conjugated equine estrogens (CEE) 0.625 mg/day (n=9) (hysterectomized women with bilateral oophorectomy) and group 2, CEE 0.625 mg/day plus chlormadinone 1 mg/day (n=9) (women with intact uterus). Changes in intraocular pressure and Schirmer's test were analyzed at baseline and three months after the treatment. Statistical analysis was performed with Student's t test for independent and paired samples., Results: There were no significant differences in intraocular pressure or Schirmer's test among groups, neither when comparing baseline and final results in each group independently., Conclusion: We could not demonstrate the effect of hormone replacement therapy on intraocular pressure and on Schirmer's test after three months of its administration.

Between August 1985 and March 2004, we performed transurethral resection of the prostate (TURP) in 18 patients with benign prostatic hyperplasia (BPH) whose prostatic volume was larger than 100 ml. We divided the patients into two groups. Group A consisted of a total of 14 cases: 10 cases whose mean prostate volume was 114 ml (100 to 137 ml) and 4 cases whose prostate volume was not measured before TURP but whose mean resected prostatic tissue weight was 113 g (105 to 118 g). Group B consisted of 4 cases whose mean prostate volume was 110 ml (101 to 133 ml). Patients in group B underwent interstitial laser coagulation of the prostate (ILCP) followed by oral chlormadinone acetate (CMA) therapy (50 mg/day); TURP was performed 6 months later, once the prostate volume had shrunk to an average of 76 ml (66 to 91 ml). Mean resected weights and operation times were: group A, 93.1 g, 66.3 min; group B, 60.5 g, 55.7 min. There were 12 blood transfusion cases (85.7%; intraoperative) in group A, and 1 (25.0%; POD 1) in group B. Accordingly, this preoperative treatment was considered a safer method of TURP for BPH 100 ml or more. There were no cases of TURP syndrome or death in either group.

The recurrence of estrus and fertility after removal of a subcutaneous chlormadinone acetate implant (CMA-I) administered to prevent estrus for 4 years, was investigated in 8 female dogs and the results compared with those for 4 untreated female dogs (control group). The sex hormones present during the estrous cycle were also investigated. There were no significant differences in the estrous cycle after removal of the implant between the CMA-I-treated group and the control group. However, although conception was achieved after mating and no uterine diseases developed in the control group, only 5 (4 dogs, 41.7%) of the 12 cases (6 dogs) in which mating took place at the second to fourth estrus after the removal of CMA-I resulted in pregnancy in the CMA-I-treated group. Furthermore, 6 (75.0%) of the 8 dogs in the CMA-I-treated group developed uterine diseases including pyometra or hydrometra. There were no significant differences in plasma progesterone, LH and prolactin levels between the non-pregnant and pregnant dogs in the CMA-I-treated group or control group. These results suggest that long-term implantation of CMA-I affects fertility after the implant is removed.

We report a case of idiopathic stuttering priapism in a 56-year-old Japanese man. We treated his recurrent priapism in stepwise fashion by withdrawal of the alpha/beta-blocker he used for hypertension, administration of low doses of an antiandrogen and baclofen, and finally by increasing the dose of antiandrogen, which lowered his testosterone to the castration level and was effective in preventing priapism. After 6 months of antiandrogen treatment, his erectile function gradually recovered to the baseline level, and he had no recurrence of priapism during the following 6 months without any medication.

Common acne is steatorrhoeic chronic disease, to which specific is, among others, the presence of blackheads, papulopustular eruptions, purulent cysts and cicatrices. Such hormonal factors belong to elements inherent in etiology of the affection. Sebaceous glands have cell receptors on their surface for androgens. In etiopathogenesis of common/simple acne, a decisive role is played by a derivative of testosterone, i.e. 5-alpha-dihydrotestosterone (DHT). However, some experts are of opinion that there is no correlation between the increased intensity of common acne and other symptoms of hyperandrogenism. Numerous authors assume, however, that common acne-affected patients may be sometimes subjected to intense reactions caused by sebaceous glands against physiological androgens concentrations. Naturally, estrogens can inhibit release of such androgens. Under physiological conditions, natural progesterone does not conduct to intensification of the seborrhea, but the activity of sebum secretion may be triggered off by its synthetic counterparts. Hormonal etiology can be very distinctly visible in the steroid, androgenic, premenstrual, menopausal acne, as well as in juvenile acne and acne neonatorum. In case of females affected by acne, hormonal therapy should be persistently supported and consulted with dermatologists, endocrinologists and gynecologists. Antiandrogenic preparations are applied, such as: cyproterone acetate concurrently administered with estrogens and, as well as not so frequently with chlormadinone acetate (independently or during estrogenic therapy).

Objectives: To determine if the vascularisation of the endometrium is dependent on the administered progestin during sequential hormone replacement therapy., Methods: Nine women received percutaneous estradiol-17 beta, 1.5 mg/day from days 1 to 24 combined with 200 mg/day micronised progesterone from days 11 to 24 of the treatment cycle. Fifteen women received percutaneous estradiol, 1.5 mg/day from days 1 to 24, combined with 10 mg/day chlormadinone acetate from days 11 to 24. Eleven women received percutaneous estradiol, 50 microg/day from days 1 to 28 combined with percutaneous norethisterone acetate, 0.3mg/day form days 14 to 28. Twelve women received intranasal estradiol, 300 microg/day from days 1 to 25 combined with 0.5 mg of promegestone from days 11 to 24. Eleven spontaneous cycling women had an endometrial biopsy during luteal phase and served as controls. Endometrial biopsies were processed routinely between days 18 and 24 and sections were immunostained using anti-CD34 antibody to identify vascular endothelial cells, which were treated with an automatic image analysis system., Results: mean (+/-S.D.) vascular density for controls was 147+/-41.5 vessels/mm(2), with mean vessel area of 143+/-60.9 microm(2). In chlormadinone users endometrial microvascular density and mean vessel area did not differ from the control group (150.2+/-58.6 and 152.9+/-70.5). The other three progestins generated a significant increase of mean vessel density, 179.6+/-51.6 with micronised progesterone, 178.5+/-67.6 with norethisterone and 179.6+/-48.4 with promegestone. The mean vessel area was lower in the latter three groups, respectively, 108.4+/-39.0, 97.5+/-46.5 and 141.6+/-66.7 microm(2), promegestone leading to non significant difference with control., Conclusion: regarding vascularisation, chlormadinone and control group gave similar patterns. Promegestone was associated with an increase of the number of vessels, as did micronised progesterone or norethisterone; the mean vascular area was the smallest in the norethisterone group.

Objective: To objectively analyze vaginal dryness in postmenopausal women., Methods: Forty healthy postmenopausal women, were divided in three groups according to the treatment they received. Group I, conjugated equine estrogens (CEE) 0.625 mg/day (n=20), group II, CEE 0.625 mg/day plus chlormadinone 1 mg/day (n=13), and group III, CEE 0.625 mg/day plus medroxyprogesterone 2.5 mg/day (n=7). Vaginal dryness intensity was analyzed using an analog visual scale, and vaginal humidity measuring the moistening in mm of a pH test strip. Both were evaluated at baseline and 3 months after the beginning of treatment. The comparison among groups and between the baseline and final results was done with Student's t-test for paired and independent samples, respectively. Pearson correlation analysis was carried out between final vaginal dryness intensity and the final moistening of the pH test strip., Results: No statistically significant differences were found in age neither in somatometric variables among the groups. In the three groups, vaginal dryness intensity significantly decreased and the pH test strip moistening significantly increased. A significant negative correlation was only found in group II (-0.690 P<0.009)., Conclusions: Vaginal dryness evaluation assessing the pH test strip moistening is an objective method to evaluate this symptom in postmenopausal women, and the results are independent of the hormone replacement therapy schedule.

Estrus was prevented with weekly oral administration of 2 mg chlormadinone acetate for 2.0 to 9.8 y in bitches and queens. Abnormalities, including mammary or uterine disorders, or both, were noted in 7 out of 14 bitches and 9 out of 24 queens during this long-term treatment.

Objectives: We conducted a postmarketing surveillance study to assess the long-term efficacy and tolerability of the oral contraceptive Belara (chlormadinone acetate 2.0 mg/ethinylestradiol 0.03 mg) in a normal outpatient setting. Another interest focused on changes in androgen-related skin and hair disorders., Methods: A total of 2620 women were enrolled in a 12-cycle clinical evaluation at 435 gynecological practices throughout Germany., Results: An unadjusted Pearl index of 0.44 was calculated. At least 9 out of 10 pregnancies were attributable to user failure, thus resulting in an adjusted Pearl index of 0.04. More than two thirds (67.3%) of the women did not experience any bleeding disorder. Patients with intermenstrual bleeding or amenorrhea at study entry reported complete relief in 61.7% and 89.3%, respectively. Women who previously suffered from spots or bad skin showed significant improvement during the observation period (85.6%). Likewise, the percentage of patients with greasy or very greasy hair decreased markedly. The vast majority of women scored the tolerability of Belara as "very good" or "good.", Conclusions: The results of this postmarketing study confirm that Belara is well tolerated and provides a high contraceptive efficacy, reliable cycle stability and beneficial effects on skin and hair.

The bioavailability of a new formulation of chlormadinone acetate (one 10 mg Lutéran tablet) was compared with that of the reference formulation (two 5 mg Lutéran tablets) in a randomised crossover open trial after single oral administration of a 10 mg dose to 12 healthy female volunteers. Measurements of chlormadinone acetate plasma samples were performed by combined gas chromatography/mass spectrometry. Blood samples were collected before administration and up to 144 hours after administration. No significant difference was found between the two formulations in pharmacokinetic parameters. The bioavailability of the two formulations was equivalent in terms of time to maximum concentration (tmax [mean tmax about 2.5 h]) and area under the concentration-time curve (AUC0-infinity) [Weslake's symmetric confidence interval: 19.24%, Schuirmann two one-sided tests procedure: p < 0.05]. No difference was found between the two formulations with regard to clinical safety parameters.

Background: Since tumor growth is determined by an imbalance between cell growth and cell death, we assessed the incidence of cell proliferation and apoptosis in biopsy specimens from patients with metastatic prostate cancer treated with endocrine therapy., Materials and Methods: In fifty-five patients with untreated metastatic prostate cancer, proliferation and apoptotic indices were determined by detection of Ki-67 immunostaining and the in situ end-labeling technique, respectively. The clinical parameters and prognosis of the patients were evaluated., Results: The proliferation index in poorly-differentiated cancer was significantly higher than that in moderately-differentiated cancer. Good-responders to hormone therapy, as assessed by the decrease in prostate-specific antigen after the endocrine therapy, were likely to have a low proliferation index. The patients with a low proliferation index had better progression-free and cause-specific survival compared to those with a high proliferation index. Proliferation indices were significantly correlated with apoptotic indices., Conclusion: Metastatic prostate cancer shows an increase of malignant potential as assessed by the number of Ki-67-positive cells and proliferation in each tumor is correlated with apoptosis.

We describe the development of a serum chlormadinone acetate (CMA) time-resolved fluoroimmunoassay (TR-FIA). We prepared haptens (3-CMO-chlormadinone acetate and 6-chloropregna-4,6-dien-17,20-diol-3-one-20-hemisuccinate), biotinylated tracers (3(biotinylaminopropylamido) 3-CMO-chlormadinone acetate and 3-(6-chloropregna-4,6-dien-17,20-diol-3-one-20-hemisuccinylamino)1-biotinylaminopropane), and immunogens necessary for eliciting two antibodies (anti-chlormadinone acetate 3-CMO/BSA and anti-chlormadinone 20-hemisuccinate/BSA). The specificity of the assay was rigorously studied to eliminate possible interference by polar metabolites of CMA, particularly 17 alpha-acetoxy-6-chloro-3beta-hydroxypregna-4,6-diene-20-one (3beta-hydroxy metabolite), employing an easy-to-use ethylene glycol chromatographic step prior to immunoassay, so as to separate the polar metabolites, in particular the 3beta-hydroxy-CMA metabolite, from the intact CMA. The choice of the anti-CMA antibody was guided by the high assay sensitivity obtained with the anti-CMA 3-CMO/BSA antibody. The detection limit was 51pg/ml. Interassay reproducibility CVs were between 2.6 and 4.5%. This TR-FIA thus appeared to be a sensitive, specific, precise, and consequently well-suited method for measurement of serum CMA during a pharmacokinetic study in women.

Study Design: A case report is presented., Objectives: To present a very rare case of orally ingested sex hormone pills inducing nondurally attached meningioma in the lumbosacral region., Summary of Background Data: Meningiomas are known to enlarge in response to female sex hormones. At this writing, few cases of nondurally based intradural meningioma have been reported. Moreover, meningiomas in the lumbosacral region are very rare. Spinal meningiomas predominantly arise in the fourth to sixth decades of life and are more common in women., Methods: The patient was a 20-year-old woman. She had undergone oral sex steroid therapy for long-term oligomenorrhea. The patient complained of intolerable lumbago and numbness in her buttocks. Nonopioid analgesics did not relieve her pain, and she was unable to walk without the aid of a walker. Radiography disclosed a lumbosacral intradural tumor., Results: Complete removal of the tumor was performed. The tumor was not adherent to the dura, and its appearance was that of a typical neurilemmoma. However, the pathologic diagnosis was meningioma., Conclusions: The tumor in the reported case may have enlarged in response to orally ingested sex steroid pills. Nondural attachment intradural meningiomas are quite uncommon. The gross appearance of the tumor during surgery was typical of neurilemmoma. All the cases reported so far, including the current case, have involved tumor located in the lumbosacral region. Care must be taken in the management of lumbosacral intradural tumors because tumors resembling neurilemmoma may in fact represent meningioma, some subtypes of which possess a high rate of recurrence.

Objectives: To determine the endometrial response in postmenopausal women treated with a sequential hormone replacement therapy (HRT) of estradiol and, either chlormadinone acetate (CA) or micronized progesterone (MP)., Methods: Three hundred and thirty-six postmenopausal women with a normal endometrium were randomized in the double-blind study. All patients received percutaneous estradiol 1.5 mg/day from day 1 to day 24 and either CA 10 mg/day or oral MP 200 mg/day from day 10 to day 24. The total duration of treatment was 18 months. Endometrial biopsies were performed before treatment and between day 18 and day 24 of the 18th month of HRT., Results: Of the 336 patients selected, 317 had a biopsy at inclusion. Of them, 244 patients (124 in the CA group and 120 in the P group) were suitable for evaluation for analysis at the 18th month. Insufficient sampling occurred in 33.9% in the CA group and 60% in the MP group (probably atrophic). No case of hyperplasia could be reported in both groups. The endometrium was atrophic in 19.5 versus 27.1%, proliferative in 3.7 versus 8.3% and secretory in 76.8 versus 62.5% in CA and MP groups, respectively. It was possible to see histological differences induced by the two progestins. The CA endometria showed fewer glands lined by a cubo-cylindrical epithelium, with an edematous stroma, compared to the MP endometria which had more glands lined by a cylindrical epithelium, stroma being poorly edematous. These figures varied in intensity due to the length of progestative impregnation, predecidualization occurring later in the CA group, with distended capillaries., Conclusions: These results show that CA 10 mg/day is a powerful progestin compared to MP 200 mg/day, on weakly estradiol-primed endometria, giving a molecule-specific histological aspect with a good endometrial safety.

Patients with prostate cancer generally respond to androgen withdrawal therapy, but progression to androgen-independence is frequently observed later. To examine whether pretreatment serum androgen status could predict disease progression in metastatic prostate cancer, pretreatment serum testosterone, histological grade, extent of bony metastasis, serum prostate-specific antigen (PSA) response to hormone therapy, and prognosis of the 40 patients with untreated metastatic prostate cancer who received endocrine therapy were evaluated. Although there were no differences in age, pretreatment PSA level, extent of bony disease and histological grade between patients with normal testosterone and those with low testosterone, PSA response after endocrine therapy was better in normal testosterone group. There was a significantly longer interval to disease progression in patients with normal testosterone than in those with low testosterone. The patients with metastatic prostate cancer with low serum testosterone were in the high risk group of worse response to endocrine therapy. Additional therapy might be considered in those patients.

Objective: The efficacy and safety of chlormadinone acetate (CA) versus micronized progesterone (P) were assessed in non-hysterectomized postmenopausal women., Materials and Methods: This was a multicenter, randomized, parallel group study with a 6-month double-blind period followed by a 12-month open period. Patients were randomized to receive every month during 18 months percutaneous 17 beta-estradiol (E(2)) 1.5 mg/day from Day 1 to 24 of treatment cycle, combined from Day 11 to 24 to either CA 10 mg/day (n=167) or P 200 mg/day (n=169). Endometrial biopsy (EB, main analysis criterion) was performed at baseline, and at Day 18-24 of the 6th and 18th cycles., Results: At Month 6, EB did not evidence any hyperplasia. EB were inadequate for assessment in 24.5% and 47.5% of patients in the CA and MP groups, respectively. CA was found to be as protective as P (96.3% and 92.0% of success). However, the hormonal status of the endometrium differed (P<0.001): a secretory endometrium was found in 81.5% of the CA patients, compared to 50.7% in the P group. These transformations resulted in predictable, cyclic bleeding in 94.5% of the CA patients, compared to only 62.3% of the P patients (P=0.0001). Unscheduled bleeding, spotting and/or metrorrhagia, were more frequent under P than under CA (17.9% and 13.7%, respectively). The beneficial effects on hot flushes were more important in the CA group than in the P (P<0.001). At Month 18, the biopsy and clinical results were similar to those obtained at Month 6. The safety profile, particularly the lipid one, was similar in both groups, except for drowsiness and dizziness, which were significantly more frequent under P than under CA., Conclusion: The progestative effects of CA on the endometrium and on menopause-related symptoms were at least as good as those of P. Moreover, CA resulted more often than P in secretory effects, and in satisfying bleeding patterns.

Objective: To demonstrate that hypoestrogenism in menopause is in part responsible for the decrease in circulating dehydroepiandrosterone sulfate (DHEA-S) and ACTH levels. To test this hypothesis, 25 postmenopausal women aged 47-60 years, were given orally conjugated equine estrogen (CEE) to study the effect on circulating DHEA-S, cortisol and ACTH., Design: A prospective, non-blinded study was performed. Hormonal levels were analyzed before and after three cycles of CEE 0.625 mg/day for 21 days followed each by chlormadinone acetate for 5 days., Results: Low baseline levels of DHEA-S increased significantly after HRT (1.71+/-0.75 to 3.3+/-1.5 micromol/l, (P<0.001). ACTH levels augmented moderately from 3.26+/-1.4 to 4.7+/-1.8 pmol/l (P<0.05) and cortisol from 350.4+/-118 to 450.8+/-144 nmol/l (P<0.01). A positive correlation was obtained between 17 beta-estradiol and ACTH (r=0.48), estradiol and cortisol (r=0.52) as well as estradiol and DHEA-S (r=0.60). In addition, the correlation was highly significant (P<0.001) between ACTH and DHEA-S at the term of HRT., Conclusion: HRT increased DHEA-S, ACTH and cortisol concentrations, which may suggest that this therapy may exert a stimulatory effect on the pituitary gland when baseline hypoestrogenism is present, but further studies are required to clarify the mechanism underlying this process.

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.