Evaluation of different antiandrogenic progestins on clinical and biochemical variables in polycystic ovary syndrome.

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.

Effect of chlormadinone acetate versus drospirenone-containing oral contraceptives on the endocrinal features of women with polycystic ovary syndrome: Systematic review and meta-analysis of randomized clinical trials.

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.

Enhanced Oral Bioavailability of Chlormadinone Acetate through a Self-Microemulsifying Drug Delivery System for a Potential Dose Reduction.

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 Cmax 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.

Experiencia en el tratamiento de la hemorragia uterina anormal en adolescentes con enfermedad renal crónica / Experience in the treatment of uterine hemorrhage in adolescents with chronic renal disease

Resumen: 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.

Abstract: 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.

[Experiencia en el tratamiento de la hemorragia uterina anormal en adolescentes con enfermedad renal crónica]. / Experience in the treatment of uterine hemorrhage in adolescents with chronic renal disease.

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.

Modification of body composition and metabolism during oral contraceptives containing non-androgenic progestins in association with estradiol or ethinyl estradiol.

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.

Third-line hormonal therapy to treat prostate cancer relapse after initial and second-line hormonal therapy: report of 52 cases and literature review.

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.

Effects of an oral contraceptive containing chlormadinone acetate and ethinylestradiol on hair and skin quality in women wishing to use hormonal contraception.

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.

Estrus induction in white rhinoceros (Ceratotherium simum).

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.

The efficacy and safety of an oral contraceptive containing chlormadinone acetate: results of a pooled analysis of noninterventional trials in adult and adolescent women.

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.

Clinical efficacy of primary combined androgen blockade for Japanese men with clinically localized prostate cancer unsuitable for local definitive treatment: a single institution experience.

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.

[Hemicentral retinal artery occlusion due to oral contraceptives]. / Hemizentralarterienverschluss bei Einnahme der "Pille"--Mitteilungen über Komplikationen von Kontrazeptiva.

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.

Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients.

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.

Beneficios no anticonceptivos de 0, 02 mg de etinilestradiol/2 mg de acetato de clormadinona administrados en un régimen de 24+4 días / Non-contraceptive benefits of 0.02 mg ethinylestradiol /2 mg chlormadinone acetate in a 24 +4 days intake regimen

Objetivo: Demostrar la influencia sobre las molestias emocionales y físicas (beneficios no anticonceptivos) experimentadas durante el primer año de uso de un anticonceptivo oral combinado (AOC) que contiene 0,02 mg de etinilestradiol (EE) y 2 mg de acetato de clormadinona (ACM) administrado en un régimen de 24 + 4 días de placebo. Diseño del estudio: Análisis adicional de las sensaciones subjetivas registradas en los diarios de 1665 participantes de un estudio de Fase III multicéntrico, no controlado, de administración múltiple, después de 13 ciclos de EE/ACM en un régimen de administración de 24 + 4 días, publicado previamente. Resultados: Se informó de menor frecuencia de molestias emocionales y físicas en el ciclo de medicación 13 en comparación con los datos en la admisión y en el ciclo 1. La incidencia de ánimo depresivo se redujo en 84,5 por ciento y 72,2 por ciento respectivamente, y la irritabilidad en 87,3 por ciento y 66,0 por ciento. Las cefaleas se redujeron en 75,5 por ciento y 74,7 por ciento, las molestias mamarias en 77,1 por ciento y 66,1 por ciento, y la dismenorrea preexistente en 77,9 por ciento y 67,6 por ciento respectivamente. El abandono prematuro del estudio a causa de las molestias fue marginal, y el perfil del sangrado fue aceptable. Conclusiones: Un AOC de baja dosis que contiene 0,02 mg de EE + 2 mg de ACM, administrado en un régimen de 24 + 4 días, reduce significativamente la mayor parte de las molestias emocionales y físicas que se presentan durante los ciclos espontáneos de las mujeres, y se combina con un adecuado perfil de sangrado.

Objective: To demonstrate the influence on physical and psychological complaints during the first year of intake of the combined oral contraceptive (COC) 0.02 mg ethinylestradiol (EE)/2 mg chlormadinone acetate (CMA), administered in a regimen of 24 days of CMA/EE intake followed by 4 days of placebo intake. Study design: The subjective feelings of non-contraceptive benefits registered in women's diaries of 1,665 subjects participating in a multicentre, uncontrolled, multiadministration, Phase III trial, published elsewhere, were analyzed post-hoc after 13 cycles intake of EE/CMA in a 24 +4 days intake regimen. Results: Emotional complaints were reported less frequently at medication cycle 13 compared with admission and cycle 1. Depressive mood was reduced by 84.5 percent and 72.2 percent, irritability by 87.3 percent and 66.0 percent; physical complaints were also reduced: headaches by 75.5 percent and 74.7 percent, breast discomfort by 77.1 percent and 66.1 percent; pre-existing dysmenorrhea by 77.9 percent and 67.6 percent. Premature termination due to complaints was only marginal, the bleeding profile was accepted. Conclusions: The low-dose COC, 0.02 mg EE/2 mg CMA, administered in a 24 +4 day regimen, reduces significantly most of the emotional and physical complaints occurring during spontaneous cycles of women, combined with an adequate bleeding profile.

Endometrial safety of a novel monophasic combined oral contraceptive containing 0.02 mg ethinylestradiol and 2 mg chlormadinone acetate administered in a 24/4-day regimen over six cycles.

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.

Endocrinological, metabolic and clinical features of treatment with oral contraceptive formulation containing ethinylestradiol plus chlormadinone acetate in nonobese women with polycystic ovary syndrome.

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.

Long-term efficacy and safety of a monophasic combined oral contraceptive containing 0.02 mg ethinylestradiol and 2 mg chlormadinone acetate administered in a 24/4-day regimen.

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.

Suppression of ovarian function by a combined oral contraceptive containing 0.02 mg ethinyl estradiol and 2 mg chlormadinone acetate given in a 24/4-day intake regimen over three cycles.

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.

Comparative effects of chlormadinone acetate and its 3alpha- and 3beta-hydroxy metabolites on progesterone, androgen and glucocorticoid receptors.

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.

Bioequivalence study of generic tablet formulations containing ethinylestradiol and chlormadinone acetate in healthy female volunteers.

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%.