Antiandrogenic Activity Research Articles

Comparison of In Vitro Endocrine Activity of Phthalates and Alternative Plasticizers.

Because of the deleterious effects of phthalates, regulations have been taken to decrease their use, and the needs for alternatives are increasing. Due to the concerns about the endocrine-disrupting properties of phthalates, it was deemed necessary to particularly investigate these effects for potential substitutes. In this study, we compared the in vitro endocrine activity of several already used potential alternative plasticizers (DEHT, DINCH, and TOTM) or new substitutes (POLYSORB® isosorbide and POLYSORB® ID 46) to one of 2 phthalates, DEHP and DINP. Effects of these chemicals on 3 common mechanisms of endocrine disruption, i.e., interaction with estrogen receptors (ER), androgen receptors (AR), or steroidogenesis, were studied using extensively used in vitro methods. In the E-Screen assay, only DEHP moderately induced MCF-7 cell proliferation; none of the other tested substances were estrogenic or antiestrogenic. No androgenic or antiandrogenic activity in MDA-kb2 cells was shown for any of the tested phthalates or alternatives. On the other hand, both DEHP and DINP, as well as DEHT, DINCH, and TOTM, disrupted steroidogenesis in the H295R assay, mainly by inducing an increase in estradiol synthesis; no such effect was observed for POLYSORB® isosorbide and POLYSORB® ID 46.

Naringenin Scaffold as a Template for Drug Designing

Natural products provide cornucopia of heterocyclic systems. The nucleus of 2- phenyl chromane is one of the important and well-known heterocycles found in the natural products. Naringenin, a plant-derived flavanone (2-phenyl chroman-4-one) belongs to the family of flavanoids. It possesses diverse biologic activities such as antidiabetic, antiatherogenic, antidepressant, antiandrogenic, antiestrogenic, immunomodulatory, antitumor, antimicrobial, anti-inflammatory, antiviral, hypolipidemic, antihypertensive, antioxidant, neuroprotective, anti-obesity, anti-Alzheimer, and memory enhancer activity. It has the potential to be used as an active pharmacophore. There have been reports of a number of molecular mechanisms underlying their beneficial activities. With emerging interest in traditional medicine and exploiting their potential based on a variety of health care systems, naringenin literature was thought to be explored. Further, this review aims to provide a new era of flavonoid-based therapeutic agents with new insights into naringenin and its derivatives as a lead compound in drug design.

Testosterone/Epitestosterone Ratios-Further Hints to Explain Hyperandrogenemia in Children with Autism.

Background: Epitestosterone [E] has for a long time been considered as a biologically inactive androgen. However, recently a distinct antiandrogenic activity of this naturally occurring endogenous epimer of Testosterone has been demonstrated. Especially the ratios of testosterone/epitestosterone (T/E) seem to be key as inhibition of epitestosterone on androgen activity was postulated. As in autism, a higher androgen activity was implied. We, therefore, suggested higher levels of T/E ratios of children with autism versus children with typical development. Methods: Urine probes of 22 girls with autism (BMI 18.7 ± 4.3; average age 12.3 ± 3.8 years) and a sample of 51 controls (BMI 17.0 ± 2.6; average age 11.9 ± 4 years), as well as 61 boys with autism (BMI 17.04 ± 2. average age 11.9 ± 2.5 years) and 61 control boys (BMI 17.0 ± 2.6; average age 11.1 ± 3.0 years), were analyzed with gas chromatography mass spectrometry. RESULTS: The average T/E ratio of all boys with autism was 2.5 ± 1.8 versus 2.4 ± 1.3 in boys with typical development, respectively. No significant difference between boys with autism versus boys with typical development could be detected (p = 0.977). In girls with autism, the average T/E ratio was 1.4 ± 0.9 versus 2.0 ± 1.4 in girls with typical development, whereby a significant difference could be detected (p = 0.0285). Further, polynomial analysis of the third degree were conducted, showing a dependence from age with reasonable coefficients of determination (0.075 < R2 < 0.22, all samples). Discussion: As encompassing steroid hormone analysis are expensive and work-intensive, we hoped to find an easily applicable biomarker to support diagnostics in autism. However, as a relatively small sample of only 22 girls with autism were analyzed and menstrual cycle and pubertal status were only partly controllable through the matching of BMI and age, the question arises if it was an incidental finding. Nevertheless, one suggestion might be that epitestosterone has the effect of a competitive inhibition on the androgen receptor, which would probably help to explain the higher prevalence of autism in boys as compared to girls. Presumably, as no significant difference was detected in boys, this effect might not be as relevant from a steroid hormone perspective, and other effects such as altered 17/20-hydroxylase activity as previously shown in boys and girls with autism seem to have more relevance. Analysis of larger samples, including plenty of metabolites and enzymatic cascades, as well as the role of backdoor pathway activity of androgen synthesis of girls with autism, are demanded in order to validate current findings of altered steroid hormones in autism.

COVID-19-The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection.

In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential.

Expression variations of two retinoid signaling pathway receptors in the rotifer Brachionus calyciflorus exposed to three endocrine disruptors.

Endocrine disruption compounds (EDC) are known to affect reproduction, development, and growth of exposed organisms. Although in vertebrates, EDCs mainly act through steroid receptors (e.g. androgen and estrogen receptors), their absence in many invertebrates suggests the involvement of another biological pathway in endocrine disruption effects. As retinoid signaling pathway is present in almost all Metazoa and its involvement in the endocrine disruption of gastropods (i.e. imposex) has been demonstrated, the present work was devoted to investigating the relative mRNA variations of two retinoid receptors genes, retinoid X receptor (RXR) and retinoid acid receptor (RAR), in the freshwater rotifer Brachionus calyciflorus exposed for 6, 12 and 24 h to flutamide, fenitrothion and cyproterone acetate, three anti-androgens known to disrupt sexual reproduction of Brachionus sp. Results revealed that fenitrothion did not affect the relative mRNA levels RXR and RAR in B. calyciflorus, whereas RXR and RAR mRNA levels could be significantly increased by 2 to 4.5-fold and from 2 to 7-fold after exposure to flutamide and cyproterone acetate, respectively. Moreover, the effects of flutamide and cyproterone acetate were measured from 6 and 12 h of exposure, respectively. Cyproterone acetate caused the highest increase of RXR and RAR mRNA levels, probably due to its progestin activity in addition to its anti-androgenic activity and the potential presence of a membrane-associated progesterone receptor as reported in Brachionus manjavacas. Consequently, although it is still difficult to evaluate the hormonal pathways involved in the endocrine disruption in Brachionus sp., this work suggests that the retinoid signaling pathway appears to be a good starting point to try to elucidate the molecular mechanisms involved in sexual reproductive dysfunction in Brachionidae.

Detection of endocrine disrupting chemicals in Danio rerio and Daphnia pulex: Step-one, behavioral screen

Anthropogenic surface and ground water contamination by chemicals is a global problem, and there is an urgent need to develop tools to identify and elucidate biological effects. Contaminants of emerging concern (CECs) are not typically monitored or regulated and those with known or suspected endocrine disrupting potential have been termed endocrine disrupting chemicals (EDCs). Many CECs are known to be neurotoxic (e.g., insecticides) and many are incompletely characterized. Behavioral responses can identify chemicals with neuroactive properties, which can be relevant to EDC mechanisms (e.g., neuroendocrine disturbances). Two freshwater species, Daphnia pulex and Danio rerio, were evaluated for swimming behavior alterations resulting from 24-hr exposure to 9 CECs: triclosan, triclocarban, chlorpyrifos, dieldrin, 4-nonylphenol, bisphenol-A, atrazine, metformin, and estrone. This is the first step in the development of a bioassay for detecting estrogenic and/or anti-androgenic activity with the goal to evaluate complex mixtures of uncharacterized contaminants in water samples. The second step, described in a subsequent report, examines transcriptome alterations following chemical exposure. Significant differences in the swimming behavior response and sensitivity were found across chemicals within a species and across species for a given chemical in this unique optical bioassay system. In the concentration ranges studied, significant behavioral alterations were detected for 6 of 9 CECs for D. pulex and 4 of 9 CECs for D. rerio. These results underscore the utility of this bioassay to identify behavioral effects of sublethal concentrations of CECs before exploration of transcriptomic alterations for EDC detection.

Effects of continuous-combined oral drospirenone- estradiol on blood pressure, body weight & lipid profile in early menopausal women.

Background & objectives:Drospirenone (DRSP) is a progestin with antimineralocorticoid and anti-androgenic activity. When administered in combination with estradiol (E2), it relieves menopausal symptoms. The aim of this study was to evaluate the effects of DRSP/E2 on the reduction of cardiovascular risk factors in menopausal women with hypertension.Methods:A retrospective study was conducted at the Clinical Center of Serbia. The participants were 64 menopausal women [mean age=49.19±4.62 yr, mean body mass index (BMI)=25.08±2.94 kg/m2, mean amenorrhoeic period=2.48±2.46 yr]. The effects of DRSP 2 mg/E2 1 mg on 24 h blood pressure (BP) variability, heart rate (HR), anthropometric characteristics and hormone and lipid levels were evaluated in early menopausal women with previously untreated stage 1 hypertension. All analyses were carried out before and after six and 12 months of therapy.Results:DRSP/E2 significantly reduced daytime BP values during six and 12 months of therapy. The reductions in systolic and diastolic BPs ranged from about −4.50 to −8.50 and from −4.00 to −5.00 mmHg, respectively. There were no significant changes in nocturnal 24 h BPs. DRSP/E2 significantly reduced HR daytime and night-time during the follow up period. DRSP/E2 significantly lowered the BMI, concentrations of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B, while high-density lipoprotein cholesterol and apolipoprotein concentration increased.Interpretation & conclusions:Continuous long-term therapy with DRSP 2 mg/E2 1 mg significantly lowered 24 h systolic and diastolic BPs and reduced the risk of cardiovascular disease in early menopausal women with stage 1 hypertension. Timely initiated menopausal hormone therapy can have beneficial effects on BP and can reduce the incidence of cardiovascular disease in menopausal women.

The role and place of azelaic acid in the routes of patients with acne vulgaris

The review presents data from foreign and domestic clinical studies on the efficacy and safety of azelaic acid (Skinoren) in the treatment of acne vulgaris. New aspects of pathogenesis are presented, an analysis of the database of systematic reviews of Russian, European, American researchers is presented, including an analysis of the database of systematic reviews of the Cochrane Systematic Review Intervention Version of the Cochrane Skin Group (2020) comparative studies on the effectiveness of azelaic acid, Skinoren and other topical topical medications for the treatment of acne vulgaris. Possibilities of monotherapy with the preparation of azaelaic acid Skinoren and variants of combined treatment, in particular, a combination of azelaic acid with topical retinoids, benzoyl peroxide, systemic and topical antibiotics for the treatment of acne of varying severity, are shown. Reliable efficacy, safety, the possibility of long-term therapy, high compliance allow us to conclude that Skinoren is highly effective in treating acne, and a number of priority complex advantages, such as the presence of anti-inflammatory, antibacterial, anti-keratinizing, antiandrogenic and anti-tyrosinase action, allow Skinoren to be considered as optimal. topical agent for long-term and safe treatment of acne and prevention of the development of post-acne symptom complex.

Assessment of the skin efficacy and acceptability of a cosmetic product in the treatment of the forearm hypertrichosis in female patients.

Treatment of unwanted body hair is a challenging area in cosmetic dermatology. Topical soy isoflavones and derivatives or eflornithine have been utilized in dermatocosmetology for their estrogenic and antiandrogenic activity. To evaluate the efficacy of a formulation containing capryloyl glycine 4% in decreasing hair growth on the forearms after topical application for 120days vs placebo. A total of 69 female patients entered the study (age 37±6). Hair growth was quantified using TrichoScan software on both forearms at 20-fold magnification (analyzed area 0.651 cm2). Hair density (number of hairs/cm2 ), density vellus hair, density terminal hair, and median length of hairs were evaluated. The data were analyzed using ANOVA for repeated measures to evaluate changes during the treatment (T0, T60, and T120) and Student's t test (placebo vs active). There was a significant decrease on hair density, median, and terminal hair at the end of the treatment in the active-treated site (P<.001) as measured by TrichoScan software. Direct comparison between active and placebo-treated sites showed no significant differences at T0, but highly significant differences at T120 (P<.001). The study shows that a cosmetic formulation based on capryloyl glycine 4% is highly effective in reducing several parameters related to hair growth and hair thickness vs placebo, thus showing efficacy in the treatment of hypertrichosis.

Estrogenic and antiandrogenic activities of methoxyflavans isolated from the fruit of Mauritia Flexuosa (Moriche Palm).

Moriche palm is consumed as both a fresh fruit and processed food in Peru and Brazil. Although its fruit contains phytoestrogens, the active compounds have not yet been identified. Therefore, we purified moriche palm extract (MPE) and identified compounds exhibiting estrogenic and antiandrogenic activities. Estrogenic activity was assessed by the estrogen-dependent growth of MCF-7 cells and increases in uterine weights in mice. Antiandrogenic activity was evaluated by 5α-reductase inhibitory activity and prostate-specific antigen (PSA) expression in LNCaP cells. In vivo antiestrogenic activity was also assessed based on testosterone-induced prostate growth in castrated mice. Four methoxyflavans were isolated from MPE and all, except for 7,4'-dihydroxy-5-methoxyflavan, promoted MCF-7 cell growth, indicating estrogenic activity. Uterine and ovary weights increased in mice orally administered MPE (400mg/kg) for 2weeks. Regarding antiandrogenic activity, among the four methoxyflavans isolated, 6,7,4'-trihydroxy-5-methoxyflavan (1 µg/ml) suppressed the mRNA and protein expression of PSA in LNCaP cells. Furthermore, prostate growth was suppressed in mice orally administered MPE (200mg/kg) for 2weeks. All methoxyflavans inhibited 5α-reductase activity with IC50 less than 10 µg/ml. Collectively, the present results demonstrated that orally administered MPE exhibited estrogenic and antiandrogenic activities. Methoxyflavans, particularly 6,7,4'-trihydroxy-5-methoxyflavan, appear to be the active compounds for these activities. PRACTICAL APPLICATIONS: The fruit of Mauritia flexuosa (moriche palm) has been used for beverages and processed foods. Although it is said to contain phytoestrogens, the active compounds have not yet been identified. In this study, we isolated and identified methoxyflavans exhibiting estrogenic and antiandrogenic activities. Among them, 6,7,4'-trihydroxy-5-methoxyflavan appeared to be the most effective compounds for these activities.

The role and place of azelaic acid in the routes of patients with acne vulgaris

The review presents data from foreign and domestic clinical studies on the efficacy and safety of azelaic acid (Skinoren) in the treatment of acne vulgaris. New aspects of pathogenesis are presented, an analysis of the database of systematic reviews of Russian, European, American researchers is presented, including an analysis of the database of systematic reviews of the Cochrane Systematic Review Intervention Version of the Cochrane Skin Group (2020) comparative studies on the effectiveness of azelaic acid, Skinoren and other topical topical medications for the treatment of acne vulgaris. Possibilities of monotherapy with the preparation of azaelaic acid Skinoren and variants of combined treatment, in particular, a combination of azelaic acid with topical retinoids, benzoyl peroxide, systemic and topical antibiotics for the treatment of acne of varying severity, are shown. Reliable efficacy, safety, the possibility of long-term therapy, high compliance allow us to conclude that Skinoren is highly effective in treating acne, and a number of priority complex advantages, such as the presence of anti-inflammatory, antibacterial, anti-keratinizing, antiandrogenic and anti-tyrosinase action, allow Skinoren to be considered as optimal. topical agent for long-term and safe treatment of acne and prevention of the development of post-acne symptom complex.

Influence of Saw palmetto and Pygeum africana extracts on the urinary concentrations of endogenous anabolic steroids: Relevance to doping analysis

BackgroundOver the counter preparations containing Saw palmetto and Pygeum africana extracts are commonly used in the treatment of benign prostatic hyperplasia with lower urinary tract symptoms. Their effects are likely due to their anti-androgenic activity, involving the interaction with type 1 and type 2 isoenzymes of the 5α-reductase family. Hypothesis/purposeFor effects similar to the above, the inhibitors of 5α-reductase (e.g., finasteride) are classified as confounding factors in the evaluation of the urinary steroid profile in sport doping. We aimed to verify whether the oral intake of products containing Saw palmetto and Pygeum africana could affect the urinary concentration of a series of steroids, not limited to those included in the “steroidal module” of the Athlete Biological Passport (ABP). Study designWe have followed the effects of a five-day administration of Saw palmetto (320 mg) and Pygeum africana (100 mg) to three non-smokers male subjects on the urinary parameters constituting the “steroidal module” of the ABP, and on the concentration of additional steroid markers. In parallel, we have also measured the urinary concentration of β-sitosterol, which is the active component of Saw palmetto and Pygeum Africana. MethodsSample collection was performed five days before starting the controlled administration study to obtain the baseline urinary steroid pattern for each subject. After this period, the three volunteers took a dose of Saw palmetto (320 mg) and Pygeum africana (100 mg) formulation orally, once a day, for five consecutive days. Urine samples were collected at different times of the day and stored at −20 °C until analysis. Samples were analyzed by a previously developed and validated method based on gas chromatography coupled to tandem mass spectrometry (GC–MS/MS). ResultsOur results show that the intake of a single oral dose of Saw palmetto and Pygeum africana for five consecutive days leads to a broader data dispersion of the target steroids' concentration levels, and, consequently, to a variation of the corresponding individual normality ranges. ConclusionThe intake of dietary supplements containing Saw palmetto and Pygeum africana could be a source of interference in the correct longitudinal evaluation of the individual steroid profile, as described in the framework of ABP. We believe their urinary levels should be monitored as it is presently done for other confounding factors of the steroidal module of the ABP.

Is Spironolactone the Preferred Renin-Angiotensin-Aldosterone Inhibitor for Protection Against COVID-19?

The high mortality of specific groups from COVID-19 highlights the importance of host-viral interactions and the potential benefits from enhancing host defenses. SARS-CoV-2 requires angiotensin-converting enzyme (ACE) 2 as a receptor for cell entry and infection. Although both ACE inhibitors and spironolactone can upregulate tissue ACE2, there are important points of discrimination between these approaches. The virus requires proteolytic processing of its spike protein by transmembrane protease receptor serine type 2 (TMPRSS2) to enable binding to cellular ACE2. Because TMPRSS2 contains an androgen promoter, it may be downregulated by the antiandrogenic actions of spironolactone. Furin and plasmin also process the spike protein. They are inhibited by protease nexin 1 or serpin E2 (PN1) that is upregulated by angiotensin II but downregulated by aldosterone. Therefore, spironolactone should selectively downregulate furin and plasmin. Furin also promotes pulmonary edema, whereas plasmin promotes hemovascular dysfunction. Thus, a downregulation of furin and plasmin by PN1 could be a further benefit of MRAs beyond their well-established organ protection. We review the evidence that spironolactone may be the preferred RASSi to increase PN1 and decrease TMPRSS2, furin, and plasmin activities and thereby reduce viral cell binding, entry, infectivity, and bad outcomes. This hypothesis requires direct investigation.

Novel complex of cosmetic ingredients with promising action in preventing hair loss and follicular aging through mechanism involving enrichment of WNT/signaling, mitochondrial activity, and stem cells maintenance.

Mechanisms involved in hair metabolism are diverse, and the availability of ingredients that normalize dysfunctions or mitigate the effects of extrinsic stress suffered daily is greatly desired by consumers to improve the aesthetic appearance of hair. In this work, we carried out a preclinical exploratory approach to evaluate the effects of a complex of nanoencapsulated active ingredients (AcPi), as well as a cosmetic formulation containing AcPi (ShPi and HtPi) in mechanisms involving hair loss and follicular aging. Human hair follicle dermal papilla cells and human scalp culture were treated with AcPi, ShPi, or HtPi and stimulated with UV radiation or testosterone for further measurement of mitochondrial biogenesis, reactive oxygen species (ROS), β-catenin, dyhidrotestosterone (DHT), collagen XVIIα1 (COL17A1), and cutaneous permeation. Our results demonstrated that AcPi prevents oxidative stress and balances mitochondial activity disturbed by exposure to UV radiation. AcPi also promoted an enrichment of WNT/β-catenin signaling pathway, stimulating hair growth, and lengthening the anagen phaseof hair cycle. ShPi and HtPi were able to prevent hair aging, minimizing the excessive degradation of COL17A1 in hair follicle exposed to UV radiation, in addition to controlling androgenic metabolism by reducing DHT production. The integral effects of AcPi have not been completely elucidated; however, these results, associated with clinical evidences, allow us to infer that this ingredient prevents follicular aging, miniaturization, and consequently hair loss by mechanisms involving energetic homeostasis maintenance, antioxidant, and anti-androgenic actions.

Co-exposures to trace elements and polycyclic aromatic compounds (PACs) impacts North American river otter (Lontra canadensis) baculum

Environmental loadings of polycyclic aromatic compounds (PACs) and trace elements are increasing in areas with marked oil and gas extraction, such as in the Athabasca oil sands region, Alberta, Canada. Some of these chemicals are recognized as potent endocrine disrupting compounds (EDCs). The impacts of co-exposure to PACs and metals on free-ranging wildlife is of considerable concern. River otters (Lontra canadensis) are sentinel species of aquatic ecosystem health. The baculum (penile bone) is an important part of the reproductive system in otters that ensures successful copulation. Although baculum health is critical to male reproductive success and is sensitive to exposure to EDCs, there is no information available regarding the impact of PAC and metal exposures on measures of baculum health. River otter baculum and livers were dissected from carcasses obtained from the fur trade. Trace element and PAC analyses were carried out in liver with matching baculums subjected to dimensional analysis, bone mineral density (BMD) and mechanical loading testing. Trace elements and select PACs exhibited both protective and deleterious effects on baculum bone health metrics. Alkylated four ring PACs were negatively associated with baculum bone material properties (ex: C4-Chrysene and C4-pyrene). The same compounds have been shown to exhibit strong anti-androgenic activities. Few comparable studies exist related to contamination and adverse effects of PACs in wild terrestrial mammals. Baculum health metrics may be an important tool to include in biomonitoring studies as to date, there are limited means to assess male reproductive performance in wildlife biomonitoring programs.

The antiandrogenic vinclozolin induces differentiation delay of germ cells and changes in energy metabolism in 3D cultures of fetal ovaries

Vinclozolin is a pesticide with antiandrogenic activity as an endocrine disruptor compound. Its effects upon the progression of primordial follicles were assessed in cultures of mouse fetal ovaries from the onset of meiotic differentiation of germ cells (13.5 days post coitum) and from both in vivo exposed mice and in vitro exposed ovaries. Exposure of ovaries to vinclozolin—at in vitro dosages ranging from 10 to 200 μM and in 3D ex vivo culture following in vivo exposure to 50 mg/kg bw/day—showed delays in meiocyte differentiation and in follicle growth, even at the lowest in vitro dose exposure. Immunofluorescent analysis showed the presence of the proteins MSY2 and NOBOX in the primary follicles but no difference in the level of protein signals or in the number of follicles in relation to treatment. However, assessing the cytological differentiation of germ cells by detecting the synaptonemal complex protein SYCP3, the exposure to vinclozolin delayed meiotic differentiation from both in vitro- and in vivo-exposed ovaries. These effects were concomitant with changes in the energy metabolism, detected as a relative increase of glycolytic metabolism in live-cell metabolic assays in exposed ovaries.

Novel toxicity of tris(1,3-dichloro-2-propyl) phosphate in adult male rats.

The widespread use of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) as a flame retardant has led to its release to the environment. Thus, the toxicological effects of TDCIPP on humans and animals are of importance. For better understanding of its potential toxicities, TDCIPP (250, 500, or 650 mg/kg/day) or vehicle control was administrated orally to adult male Wistar-Imamichi rats for 7 days. After the final administration of compounds, organ weights, histopathology, blood biochemistry, and hematology were examined. Hepatic toxicity was observed at doses ≥ 500 mg/kg/day of TDCIPP, and renal toxicity was observed at 650 mg/kg/day. The anti-androgenic activity of TDCIPP was previously confirmed in vitro and in vivo, but weights of epididymis, an androgen-dependent organ, were not affected by TDCIPP treatment in adults. Serum alkaline phosphatase activity was significantly decreased in all TDCIPP-treated rats independent of dose. Hemoglobin concentration, hematocrit, red blood cell count, and reticulocyte count were decreased in all TDCIPP-treated rats, but mean corpuscular volume, total iron-binding capacity, and serum iron were normal, suggesting that renal anemia was caused by TDCIPP. Together with previous reports on effects of anti-androgenic substances on red blood cell indices, anemia caused by TDCIPP could be due to its anti-androgenic activity. These considerations will contribute to further assessment of the toxicity of the compound.

Synthesis and Study of Some 17a-aza-D-homo Steroids as 5α-Reductase Inhibitors.

Tremendous advances have been made in the development of new pharmacotherapuetic agents and less invasive techniques to help men with lower urinary tract symptoms. The use of 5α-reductase inhibitor (5-ARI) is restricted to the patients with large prostate volumes, whose symptoms are refractory to antiandrogens or α-adrenergic blockers. Out of the various synthesized 5-reductase inhibitors with different substituents on the steroidal nucleus, esters have been found to exhibit high anti-androgenic activity. In our attempt to find new, safer and potent 5-ARI and our continued interest in azasteorids, esters of 17a-Aza-D-homo-5-androsten-3β-ol with synergistic effect were synthesized and characterized using different analytical techniques. The compounds were evaluated for their 5α-reductase inhibitory activity in-vivo by their effect on serum androgen level by ELISA assay procedure. The interaction with receptors was studied using an advanced docking programme to predict the correlation of the synthesized compounds with actual biological activity. The target compounds (6-12) showed increased anti-androgenic activity as compared to finasteride and control, which imply that the target compounds are effective in inhibiting 5α-reductase. Particularly, compound 6 showed the highest inhibitory activity and greater affinity for the 5- AR receptor with the highest dock score. The results of these studies when compared with Finasteride showed increased solubility and dissolution of target compound 6. Compound 6 showed immense potential with improved efficacy and better bioavailability, thus makes it a suitable candidate for further studies and optimal formulation.

Contraceptive and therapeutic effects of combined oral contraceptive with drospirenone

The article presents data on the clinical and contraceptive capabilities of an estrogen-progestogen drug containing drospirenone (Midiana). By its pharmacological properties, drospirenone is close to endogenous progesterone and has gestagenic, antiandrogenic and antimineralocorticoid action. With a high affinity for progesterone receptors, drospirenone suppresses ovulation, reliably protects against unwanted pregnancy and provides an additional contraceptive effect. Combined oral contraceptives with drospirenone, taking into account their antiandrogenic and antimineralocorticoid properties, are successfully used in the treatment of premenstrual syndrome, polycystic ovaries, hyperandrogenism and in the prevention of endometrial hyperplastic processes without causing significant weight change.

Anti-androgenic, anti-oxidant and anti-apoptotic effects of the aqueous and methanol extracts of Pterorhachis zenkeri (Meliaceae): Evidence from in vivo and in vitro studies.

The aim of this study was to evaluate the effects of Pterorhachis zenkeri (Meliaceae) on sex organ growth in immature male rats and, oxidative stress and apoptosis markers in CCL-97 (R2C) Leydig cells. For the in vivo studies, 70 immature male Wistar rats (n=10/group) were treated for 2 or 4weeks with: distilled water (10ml/kg, per os) plus soya oil (1ml/kg, sc), bicalutamide (10mg/kg, per os), aqueous or methanol extract of P. zenkeri (10mg/kg or 62mg/kg, per os) or testosterone propionate (3mg/kg, sc). After each treatment period, body and sexual organ weights, plasmatic testosterone, total proteins and total cholesterol levels were measured. In the in vitro test, the effects of the methanol extract of P. zenkeri on cell viability, apoptosis, reactive oxygen species (ROS) production, intracellular calcium release and caspases 3/9 were assessed using CCL-97 Leydig cells. Pterorhachis zenkeri extracts decreased sex organ weights, plasmatic testosterone and protein levels in rats. In the in vitro studies, P. zenkeri inhibited apoptosis, ROS production, calcium release and caspase 3/9 activities. These results suggest that P. zenkeri has anti-androgenic, anti-oxidant and anti-apoptotic activities with methanol extract being the most active and could be an effective alternative for the management of androgen-related diseases.