Effects of oral contraceptives on metabolic profile in women with polycystic ovary syndrome: A meta-analysis comparing products containing cyproterone acetate with third generation progestins.

BACKGROUND: Although oral contraceptives (OCs) are the most common treatment in women with polycystic ovary syndrome (PCOS), their effects and safety on the metabolic profiles of these patients are relatively unknown. In this meta-analysis the effects of the different durations (from 3months to 1year) of OC treatment using cyproterone acetate (CA) or third generation progestins on metabolic profile of patients with PCOS were assessed. MATERIALS AND METHODS: PubMed, Scopus, Google Scholar and ScienceDirect databases (2001-2015) were searched to identify clinical trials investigating the effects of OC containing CA or third generation progestins on metabolic profiles of women with PCOS. Both fixed and random effect models were used. Subgroup analyses were performed based on the progestin compounds used and on duration of treatment. RESULTS: Oral contraceptive (OC) use was found to be associated with a worsening in lipid profiles but no changes were observed in other metabolic outcomes, including body mass index (BMI), fasting blood glucose (FBG), fasting insulin, homeostatic model for measuring insulin resistance (HOMA-IR) and in blood pressure (BP) values. All studied OCs showed similar effects on lipid profiles but with different timings, with products containing CA, requiring 6months to raise high density lipoprotein-cholesterol (HDL-C) levels and 12months to increase triglycerides (TG). On the contrary, products containing drospirenone (DRSP) or desogestrel (DSG) increased HDL-C after only 3months but determined elevations of TG after 6months. All OCs induced an increase in low density lipoprotein-cholesterol (LDL-C) after 12months of use. CONCLUSIONS: The study shows that, in women with PCOS, OC use is associated with significant changes in lipid profiles, including elevation not only in HDL-C but also in TG and LDL-C. All OCs studied showed similar effects but with different timings, with products containing CA generally requiring more prolonged use to increase serum lipids. Instead, OC use does not affect body weight, BP or glucose levels, with only some minor increase of fasting insulin levels.

Antiandrogens act as selective androgen receptor modulators at the proteome level in prostate cancer cells.

Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic responses dependent upon cellular context.

Effects of steroidal and non-steroidal antiandrogens on wild-type and mutant androgen receptors.

BACKGROUND: Molecular basis for secondary antiandrogen therapy in prostate cancer with mutant androgen receptors (ARs) is not fully elucidated. MATERIALS AND METHODS: Effects of steroidal and non-steroidal antiandrogens on transcriptional activities of wild-type and mutant (W741C, T877A, and W741C+T877A) ARs were measured. Crystal structure analysis and docking studies were performed using Molecular Operating Environment (MOE) package. RESULTS: DHT-induced transcriptional activity of the T877A mutant and the W741C mutant was suppressed by bicalutamide and hydroxyflutamide, respectively. Nilutamide suppressed the W741C mutant and the double mutant. Cyproterone acetate modestly inhibited the W741C mutant and the double mutant. The structural studies suggested that nilutamide and cyproterone acetate retain their antiandrogenic properties against both the W741C mutant and the double mutant due to fact that mutation W741C does not permit formation of key hydrophobic interaction between ligand and AR ligand binding domain, which is necessary for their conversion into agonists. CONCLUSIONS: Switching antiandrogens may be reasonable in prostate cancer with mutant ARs.

Crystal structure of the T877A human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design.

Cyproterone acetate (CPA) is a steroidal antiandrogen used clinically in the treatment of prostate cancer. Compared with steroidal agonists for the androgen receptor (AR) (e.g. dihydrotestosterone, R1881), CPA is bulkier in structure and therefore seemingly incompatible with the binding pockets observed in currently available x-ray crystal structures of the AR ligand-binding domain (LBD). We solved the x-ray crystal structure of the human AR LBD bound to CPA at 1.8A in the T877A variant, a mutation known to increase the agonist activity of CPA and therefore facilitate purification and crystal formation of the receptor.drug complex. The structure demonstrates that bulk from the 17alpha-acetate group of CPA induces movement of the Leu-701 side chain, which results in partial unfolding of the C-terminal end of helix 11 and displacement of the loop between helices 11 and 12 in comparison to all other AR LBD crystal structures published to date. This structural alteration leads to an expansion of the AR binding cavity to include an additional pocket bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880. Further, we found that CPA invokes transcriptional activation in the L701A AR at low nanomolar concentrations similar to the T877A mutant. Analogous mutations in the glucocorticoid receptor (GR) and progesterone receptor were constructed, and we found that CPA was also converted into a potent agonist in the M560A GR. Altogether, these data offer information for structure-based drug design, elucidate flexible regions of the AR LBD, and provide insight as to how CPA antagonizes the AR and GR.

Evaluation of an eucalyptus oil containing topical drug delivery system for selected steroid hormones.

In the present study the permeation and the chemical stability of 17-beta-estradiol, progesterone, cyproterone acetate and finasteride incorporated in an eucalyptus oil containing microemulsion system have been investigated. The formulations contained 1% (w/w) of the steroid hormones. Self diffusion coefficients determined by pulsed-field-gradient spin echo NMR spectroscopy were used to characterise the microemulsion. From these results a bicontinuous structure is proposed for the multicomponent system. However a correlation between the self diffusion of the hormones in the vehicle and the transdermal flux was not indicated. Explanations for this were self assembling, formation of aggregates between the components of the microemulsion and drugs and different effects because of different solubility of the drugs. By addition of certain polymers the skin permeation rates could be improved with exception of cyproterone acetate. Beside standard diffusion experiments, the residual drug content in the skin was investigated. Drug stability was monitored by analysing the steroid hormone content in the different formulations over an observation period of 6 weeks and could be improved by polymers. In addition, viscosity measurements were performed. They indicated an influence of the polymers and drugs on the viscosity in all formulations.

Cyproterone acetate: a genotoxic carcinogen?

Cyproterone acetate, a widely used synthetic progestagen with antiandrogenic activity, is known for years to produce liver tumours in rats, with a higher incidence in females. This effect was attributed to a rodent-specific tumour promoting mode of action based on the detection of a strong hepato-mitogenic activity of cyproterone acetate. However, more recent studies have demonstrated that cyproterone acetate is sex-specifically activated to (a) DNA-damaging intermediate(s) in the liver of female rats which result in the formation of DNA adducts, induction of DNA repair, and increased levels of micronuclei and gene mutations. Consistent with a sex-specific genotoxicity, cyproterone acetate showed a tumour-initiating potential in a liver foci assay with female rats but not with male rats. Most important, cyproterone acetate was found to induce formation of DNA adducts in primary cultures of human hepatocytes indicating that human liver cells have the capacity to activate cyproterone acetate to genotoxic intermediates. However, the overall assessment of the preclinical data presented in this review suggests that induction of liver tumours in female rats most probably depends on both, genotoxic and mitogenic effects which would suggest a non-linear mode of action with regard to tumour formation. With the exception of DNA adduct formation all other adverse effects induced by cyproterone acetate in rat liver, including gene mutations and liver tumours, can be detected at very high dose levels only. Hence, a cancer risk estimate based on a simple linear extrapolation from high dose to low exposure conditions of recommended clinical use would be questionable. Human data from pharmacoepidemiological studies that specifically addressed the question of possible liver cancer risk in patients treated with cyproterone acetate do in principle support this interpretation. In agreement with these considerations the regulatory authorities of the European Union came to the common conclusion that a possible cancer risk associated with the clinical use of cyproterone acetate, if any, appears to be low and the risk-benefit ratios for the currently authorised indications remain favourable.

Experience with cyproterone acetate in the treatment of precocious puberty.

The authors review their experience (1967-present) in the use of cyproterone acetate (CPA) in precocious puberty. CPA was found effective in persistently suppressing pituitary gonadotropic secretion when administered orally at a dose of 50 mg b.i.d. (70-100 mg/d). After the introduction of gonadotropic analogues (GnRHa) for treatment of central precocious puberty, short term use of CPA was found useful to counteract the initial stimulatory effect of the GnRHa as well as an adjunct drug in case of very active adrenarche causing advanced bone age during GnRHa treatment. The final heights of girls treated with CPA and girls treated with D-Trp6-LHRH were found comparable: 157.8+/-5.1 cm vs 159.6+/-6.3 cm, respectively. The main adverse effects were occasional fatigue due to partial adrenal insufficiency with CPA and gynecomastia in a few boys. Liver function tests were normal in all patients with the exception of one boy with severe hypothalamic disease, including precocious puberty, who developed liver cirrhosis 3 years after stopping CPA following 5 years treatment. Other indications for CPA treatment during childhood and adolescence, such as fast puberty, congenital adrenal hyperplasia and acne, are also mentioned.

The role of antiandrogens in hormone replacement therapy.

The most widely used antiandrogens in clinical practice are cyproterone acetate, a derivative of 17-hydroxyprogesterone, and dienogest, a 19-norprogestin. An established sequential preparation for hormone replacement therapy (HRT) consists of 11 days of 2 mg estradiol valerate, 10 days of 2 mg estradiol valerate with 1 mg cyproterone acetate, followed by a 7-day drug-free interval (Climen, Schering AG, Berlin, Germany). Cyproterone acetate is highly progestogenic, has no androgenic properties, and is antiandrogenic above a certain dose. Cyproterone acetate does not counteract the estrogenic effects of estradiol valerate in Climen. This therapy, therefore, has optimal effects on lipid metabolism and coronary heart disease risk, protects the endometrium and reduces menopausal symptoms, preserves bone and reduces osteoporotic fracture risk, and has antiandrogenic effects on the skin and other androgen-sensitive epidermal structures. Dienogest, on the other hand, will soon be introduced in a continuous combined HRT. Dienogest has a 17 alpha-cyanomethyl group instead of the 17 alpha-ethinyl group typical of the common 19-nortestosterone derivatives. It is also referred to as a hybrid progestogen because it has pharmacodynamic properties (e.g. antiandrogenicity) in common with progesterone derivatives. A fixed formulation containing 2 mg estradiol valerate and 2 mg dienogest (Climodien) for continuous combined HRT has been developed. This formulation had excellent effects on vasomotor and neurovegetative symptoms. The bleeding pattern was generally highly satisfactory and similar to that with Kliogest, as were the results of endometrial biopsies after 12 cycles of treatment. Lipid metabolic changes may be interpreted as beneficial. Dienogest had no adverse effects on the vasorelaxant effect of estradiol valerate in postmenopausal women, as shown by markers of vascular function. Neuropsychological studies utilizing evoked potentials showed shortening effects on sleep latency and an improvement in cognitive information processing. Continuous combined HRT with dienogest, therefore, may come to be regarded as the HRT of choice in postmenopausal patients with mood defects. In summary, HRT with antiandrogenic progestogens has its specific indications with respect to preserving metabolic estrogenicity, specific antiandrogenic effects and specific effects on vigilance and mood disorders.

Induction of micronuclei and of enzyme-altered foci in the liver of female rats exposed to progesterone and three synthetic progestins.

Progesterone (PG) and three structurally similar synthetic progestins-norethisterone (NE), allylestrenol (AE), and dydrogesterone (DG)-have been compared for their ability to induce the formation of micronuclei and of enzyme-altered foci in the liver of female rats. In the micronucleus assay, carried out in rats given a single p.o. dose of 100 mg kg-1 3 days before partial hepatectomy and sacrificed for cell sampling 2 days later, the frequency of micronucleated hepatocytes was 3.5-fold higher than in controls with PG, 2.8-fold with DG, 2.2-fold with NE and 2.1-fold with AE, but the increase was statistically significant only for PG. In the liver foci assay, performed to evaluate the tumor initiating activity of p. o. dosing with 100 mg kg-1 once a week for 6 successive weeks, the values of the number and area of gamma-glutamyltranspeptidase-positive foci were, as compared to controls, 15.9- and 100-fold higher with NE, and 13.9- and 52-fold higher with AE, but only the increase of area produced by NE was statistically significant; PG and DG did not display in this test any activities. Considered together with previous findings, these results suggest that NE might be biotransformed in the liver into reactive species and thus behave as a weak genotoxic agent.