Prospective study of fertility-sparing treatment with chlormadinone acetate for endometrial carcinoma and atypical hyperplasia in young women.

OBJECTIVE: To confirm that the efficiency of the use of chlormadinone acetate for 6 months to obtain remission of atypical hyperplasia or endometrial carcinoma is comparable to that of the use of other fertility-sparing treatments. METHOD: The present study is based on the PREFERE prospective registry. All the patients received 3 or 6 months of chlormadinone acetate and were evaluated by hysteroscopic resection and pipelle sampling every 3 months. RESULTS: Ninety-four patients were included. Seventy-nine patients achieved complete remission at 6 months (84%). No patients stopped treatment because of a lack of tolerance. Twenty-four per cent of the patients achieved a live birth. CONCLUSION: Chlormadinone acetate is an effective and well-tolerated fertility-sparing treatment. Its benefits over other progestins are its tolerability, and its absence of contraindications, which make it a good choice for patients with thromboembolism and high vascular risk.

Preliminary report of patients with meningiomas exposed to Cyproterone Acetate, Nomegestrol Acetate and Chlormadinone Acetate - Monocentric ongoing study on progestin related meningiomas.

INTRODUCTION: The relationship between meningioma and progestins has not been elucidated. Meningioma regression after acetate cyproterone (CA) withdrawal has been reported. Our purpose was to evaluate the meningioma evolution after withdrawal of progestins in patients who underwent long-term exposure to CA, nomegestrol acetate (NA), chlormadinone acetate (ChlA). METHODS: Our study retrospectively included 69 patients with intracranial meningioma and exposed to one of these 3 progestins between December 2006 and March 2019. In each patient, clinico-radiological (MRI) follow-up was performed every 6 months after diagnosis and treatment withdrawal recommendation. Statistical analyses were applied to compare tumor location and respect of prescription rules between the 3 groups. RESULTS: The mean hormonal exposure was 16 years in CA group (n = 46), 16 years in NA group (n = 12) and 9.7 years in ChlA group (n = 11). A higher rate of "out of label" use was observed in the CA group (p = 0.003). Multiple meningiomas were demonstrated in more than 60% of cases in each group. Anterior skull base location was noted in 60.5% of cases in CA group, 25% of cases in NA group and 36.7% of cases in ChlA group (p = 0.05). Incomplete tumor regression was recorded in 11 cases of CA group and in 2 cases of ChlA group. CONCLUSION: In CA group, our results suggest a strong relationship between this treatment and development of intracranial meningioma. In presence of voluminous asymptomatic meningioma, treatment can be delayed due to the potential regression after withdrawal. On the contrary in NA and ChlA groups, further studies are needed.

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

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

Progestin-associated shift of meningioma mutational landscape.

Background: Meningiomas are the most common primary tumor of the central nervous system. The relationship between meningioma and progestins is frequently mentioned but has not been elucidated. Patients and methods: We identified 40 female patients operated for a meningioma after long-term progestin therapy and performed targeted next generation sequencing to decipher the mutational landscape of hormone-related meningiomas. A published cohort of 530 meningiomas in women was used as a reference population. Results: Compared with the control population of meningiomas in women, progestin-associated meningiomas were more frequently multiple meningiomas [19/40 (48%) versus 25/530 (5%), P < 10-12] and located at the skull base [46/72 (64%) versus 241/481 (50%), P = 0.03]. We found a higher frequency of PIK3CA mutations [14/40 (35%) versus 18/530 (3%), P < 10-8] and TRAF7 mutations [16/40 (40%) versus 140/530 (26%), P < 0.001] and a lower frequency of NF2-related tumors compared with the control population of meningiomas [3/40 (7.5%) versus 169/530 (32%), P < 0.001]. Conclusion: This shift in mutational landscape indicates the vulnerability of certain meningeal cells and mutations to hormone-induced tumorigenesis. While the relationship between PIK3CA mutation frequency and hormone-related cancers such as breast and endometrial cancer is well-known, this hormonally induced mutational shift is a unique feature in molecular oncology.

Reproductive and transcriptional effects of the antiandrogenic progestin chlormadinone acetate in zebrafish (Danio rerio).

Chlormadinone acetate (CMA) is a frequently used progestin with antiandrogenic activity in humans. Residues may enter the aquatic environment but potential adverse effects in fish are unknown. While our previous work focused on effects of CMA in vitro and in zebrafish eleuthero-embryos, the present study reports on reproductive and transcriptional effects in adult female and male zebrafish (Danio rerio). We performed a reproductive study using breeding groups of zebrafish. After 15 days of pre-exposure, we exposed zebrafish to different measured concentrations between 6.4 and 53,745 ng/L CMA for 21 days and counted produced eggs daily to determine fecundity. Additionally, transcriptional effects of CMA in brains, livers, and gonads were analyzed. CMA induced a slight but statistically significant reduction in fecundity at 65 ng/L and 53,745 ng/L compared to pre-exposure. Furthermore, we observed differential expression for gene transcripts of steroid hormone receptors, genes related to the hypothalamic-pituitary-gonadal axis, and steroidogenesis. In particular, we found a significant decrease of transcript levels of vitellogenin (vtg1) in ovaries and liver, and of cyp2k7 in the liver of males, as well as a significant increase of transcripts of the progesterone receptor (pgr) in testes, and cyp2k1 in the liver of females. The observed effects were weaker than those of other very potent progestins, which is probably related to the lack of interaction of CMA with the zebrafish progesterone receptor.

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

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

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.

Rapid relapse in depression following initialization of oral contraception with ethinyl estradiol and chlormadinone acetate.

OBJECTIVE: Female sexual hormones (estrogens and gestagens) may affect neurocognitive functioning and mood. Thus, the use of oral hormonal contraceptives (OHC) bears the risk of psychiatric adverse drug reactions such as depression and psychosis. However, the available empiric evidence regarding this connection is conflicting, and, moreover, female sex hormones seem to feature also mood-stabilizing and antidepressive effects. Hence, individual susceptibility factors and preparation-specific pharmacologic properties might play a pivotal role in the development of mood disturbances related to OHC. Single case reports provide empiric data for further systematic approaches. METHODS: A clinical case is presented and discussed. RESULTS: A 36-year-old female patient with recurrent major depressive disorder developed rapid relapse in depression after initialization of OHC with ethinyl estradiol 30 µg/chlormadinone acetate 2 mg. This OHC combination was described to particularly feature positive effects on depressive mood. CONCLUSIONS: OHC may induce serious mood disturbances and should be administered with care, particularly in patients with affective disorders.

Effects of combined oral contraceptives containing levonorgestrel or chlormadinone on the endothelium.

BACKGROUND: Although the use of combined oral contraceptives (COCs) is associated with an increased risk of arterial and venous thromboembolic events, less is known about the impact of COCs on endothelial function. The present study evaluated the effects on the endothelium of healthy women of combinations of 30 mcg ethinylestradiol (EE)/2 mg chlormadinone acetate (CMA) and 30 mcg EE/150 mcg levonorgestrel (LNG). STUDY DESIGN: Sixty-four healthy women were evaluated, 21 using a nonhormonal contraceptive method (control) and 43 using COCs, randomized to EE 30 mcg /CMA 2 mg or to EE 30 mcg/LNG 150 mcg. Anthropometric parameters, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), ultrasound markers of endothelial function, flow-mediated dilation (FMD) of the brachial artery, intima-media thickness (IMT) and common carotid artery stiffness were measured at randomization and 6 months later. RESULTS: Relative to baseline, EE/CMA users showed a significant reduction in mean DAP at 6 months (p=.02), and EE/LNG users showed a significant increase in mean IMT (p=.02) and a significant reduction in mean FMD (p=.01) at 6 months. DAP at 6 months was significantly lower in COC users than in controls (p=.01). Intergroup evaluations showed that, at 6 months, mean SAP (p=.02) was significantly lower in EE/LNG users than in controls (p=.02) and that mean DAP was significantly lower in EE/CMA (p<.01) and EE/LNG (p=.01) users than in controls. EE/LNG users experienced a mean FMD reduction almost threefold greater than that of EE/CMA users. Compared to controls, EE/LNG users experienced a 7.5-fold greater reduction in mean FMD. CONCLUSIONS: COC containing LNG is associated with more pronounced changes in the FMD and IMT of healthy women than a COC containing CMA and nonhormonal contraception. Further studies are needed to determine whether these differences may lead to higher risk of arterial thromboembolic events.

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

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

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.

Ethinylestradiol/Chlormadinone acetate: dermatological benefits.

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

Ethinylestradiol/Chlormadinone acetate for use in dermatological disorders.

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

[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.

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

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

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.

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

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

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.

Six-month evaluation of the benefits of the low-dose combined oral contraceptive chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg in young women: results of the prospective, observational, non-interventional, multicentre TeeNIS study.

BACKGROUND: In clinical trials and non-interventional studies encompassing > 50,000 women, the monophasic, low-dose combined oral contraceptive (OC) chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg (CMA/EE) has been shown to have various non-contraceptive benefits, as well as contraceptive efficacy and good tolerability. However, there is a paucity of data on use of this OC in young women. OBJECTIVE: To investigate the relevance of, and changes in, cycle disorders, dysmenorrhoea and skin problems in addition to the efficacy and tolerability of CMA/EE in young women. METHODS: In this prospective, observational, non-interventional, multicentre study (TeeNIS [Teenager in Non-Interventional Study 2 mg CMA/0.03 mg EE]), young women (< or =20 years of age) were administered CMA/EE (Belara) once daily for 21 days (one blister strip), followed by either a 7-day pill-free interval (conventional cycle regimen; 89.3%) or a pill-free interval after two blister strips or more (extended cycle regimen; 3.7%), over a 6-month treatment period. Data on the mode of administration were missing for 7.1% of patients. The study included a safety population of 7462 patients (the efficacy population consisted of 6885 patients) from 886 gynaecological centres throughout Germany. RESULTS: Compared with baseline, CMA/EE intake resulted in significant reductions in the numbers of patients with cycle disorders, i.e. spotting (-46%), breakthrough bleeding (-64%), heavy bleeding (-95%) and absence of any bleeding (secondary amenorrhoea; -76%) [all p < or = 0.001], and with dysmenorrhoea (-56%) [p < or = 0.001]. Similarly, there was a significant decrease in the number of patients who used analgesics (-75%), had dysmenorrhoea-associated symptoms (back pain [-69%], headache [-70%], nausea/vomiting [-85%], diarrhoea [-80%], mood swings [-75%] or absence from school/job due to dysmenorrhoea [-92%]), or were restricted in their leisure/sporting activities because of dysmenorrhoea (-83%) [all p < or = 0.001]. Another major benefit of CMA/EE was a significant reduction in the number of patients with skin problems (acne and acne-prone skin) [-55%; p < or = 0.001]. In parallel, the number of patients who needed dermatological treatment (-67%; p < or = 0.001) and concealer cosmetics (-55%; p < or = 0.001) was significantly reduced, and significantly fewer patients felt that their self-esteem was restricted due to skin problems (-67%; p < or = 0.001). There were no relevant weight changes during the observation period; mean bodyweight remained virtually constant (mean weight change <1 kg). At final assessment, physicians' expectations were either 'completely fulfilled' or 'exceeded' with regard to cycle stability, regular bleeding, dysmenorrhoea, effects on weight, and skin problems in 78-95% of patients. CMA/EE provided high contraceptive efficacy with an unadjusted Pearl index of 0.25, calculated from 41 601 cycles of exposure; seven out of eight pregnancies were attributable to user failure, thus resulting in an adjusted Pearl index of 0.03. The tolerability of CMA/EE was excellent, with no unexpected adverse effects. CONCLUSIONS: This observational, non-interventional study in young women showed that CMA/EE had a significantly beneficial effect on cycle disorders, dysmenorrhoea and skin disorders, and confirmed the good efficacy and tolerability of this combined OC.