Early-life exposure to sex hormones promotes voluntary ethanol intake in adulthood. A vulnerability factor to drug addiction.

While there is extensive research on alcohol dependence, the factors that make an individual vulnerable to developing alcoholism haven't been explored much. In this study, we aim to investigate how neonatal exposure to sex hormones affects alcohol intake and the regulation of the mesolimbic pathway in adulthood. The study aimed to investigate the impact of neonatal exposure to a single dose of testosterone propionate (TP) or estradiol valerate (EV) on ethanol consumption in adult rats. The rats were subjected to a two-bottle free-choice paradigm, and the content of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (NAcc) was measured using HPLC-ED. The expression of critical DA-related proteins in the mesolimbic pathway was evaluated through RT-qPCR and western blot analysis. Supraphysiological neonatal exposure to EV or TP resulted in increased ethanol intake over four weeks in adulthood. In addition, the DA and DOPAC content was reduced and increased in the NAcc of EV and TP-treated rats, and ß-endorphin content in the hypothalamus decreased in EV-treated rats. The VTA µ receptor and DA type 2 form short receptor (D2S) expression were significantly reduced in EV and TP male rats. Finally, in an extended 6-week protocol, the increase in ethanol consumption induced by EV was mitigated during the initial two hours post-naloxone injection. Neonatal exposure to sex hormones is a detrimental stimulus for the brain, which can facilitate the development of addictive behaviors, including alcohol use disorder.

Topical estrogen, testosterone, and vaginal dilator in the prevention of vaginal stenosis after radiotherapy in women with cervical cancer: a randomized clinical trial.

BACKGROUND: We aimed to evaluate the effects of different therapeutic options to prevent the evolution of vaginal stenosis after pelvic radiotherapy in women with cervical cancer. METHODS: open-label randomized clinical trial of 195 women, stage I-IIIB, aged 18-75 years, using topical estrogen (66), topical testosterone (34), water-based intimate lubricant gel (66), and vaginal dilators (29) to assess the incidence and severity of vaginal stenosis after radiotherapy at UNICAMP-Brazil, from January/2013 to May/2018. The main outcome measure was vaginal stenosis assessed using the Common Terminology Criteria for Adverse Events (CTCAE) scale and percental changes in vaginal volume. The women were evaluated at four different times: shortly after the end of radiotherapy, and four, eight, and 12 months after the beginning of the intervention. Statistical analysis was carried out using Symmetry test, Kruskal-Wallis test and multiple regression. RESULTS: the mean age of women was 46.78 (±13.01) years, 61,03% were premenopausal and 73,84% had stage IIB-IIIB tumors. The mean reduction in vaginal volume in the total group was 25.47%, with similar worsening in the four treatment groups with no statistical difference throughout the intervention period. There was worsening of vaginal stenosis evaluated by CTCAE scale after 1 year in all groups (p < 0.01), except for the users of vaginal dilator (p = 0.37). CONCLUSIONS: there was a reduction in vaginal volume in all treatment groups analyzed, with no significant difference between them. However, women who used vaginal dilators had a lower frequency and severity of vaginal stenosis assessed by the CTCAE scale after one year of treatment. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials, RBR-23w5fv . Registered 10 January 2017 - Retrospectively registered.

Neonatal programming with sex hormones: Effect on expression of dopamine D1 receptor and neurotransmitters release in nucleus accumbens in adult male and female rats.

Steroid sex hormones produce physiological effects in reproductive and non-reproductive tissues, such as the brain. In the brain, sex hormones receptors are expressed in cortical, limbic and midbrain areas modulating memory, arousal, fear and motivation between other behaviors. One neurotransmitters system regulated by sex hormones is dopamine (DA), where during adulthood, sex hormones promote neurophysiological and behavioral effects on DA systems such as tuberoinfundibular (prolactin secretion), nigrostriatal (motor circuit regulation) and mesocorticolimbic (driving of motivated behavior). However, the long-term effects induced by neonatal exposure to sex hormones on DA release induced by D1 receptor activation and its expression in nucleus accumbens (NAcc) have not been fully studied. To answer this question, neurochemical, cellular and molecular techniques were used. The data show sex differences in NAcc DA extracellular levels induced by D1 receptor activation and protein content of this receptor in male and female control rats. In addition, neonatal programming with a single dose of TP increases the NAcc protein content of D1 receptors of adult male and female rats. Our results show new evidence related with sex differences that could explain the dependence to drug of abuse in males and females, which may be associated with increased reinforcing effects of drugs of abuse.

Inhibitory Effect of Artemisinin on Testosterone Propionate Induced Benign Prostatic Hyperplasia.

BACKGROUND: Benign prostate hyperplasia [BPH] is an abnormal growth of prostate observed commonly in elderly males. Artemisinin has been reported to reduce the levels of testosterone. OBJECTIVE: This study is designed to evaluate the efficacy of Artemisinin on testosterone propionate [TP] induced benign prostate hyperplasia. MATERIALS AND METHODS: Male Wistar albino rats [n=24] were separated into four groups of six rats each. Group I served as control and distilled water using tween 80 as an emulsifying agent was administered subcutaneously. BPH was induced by testosterone propionate 3mg/kg [Group II], S.C. daily for 28 days. Group III was BPH + Finasteride treated group (10mg/kg orally for 28 days) and BPH + Artemisinin treated group (Group IV) (50 mg/kg orally for 28 days). RESULT: The study results showed significantly high levels of serum prostatic acid phosphatase (PAP), lactate dehydrogenase (LDH) and an elevation in prostate weight and prostatic index in Group II (BPH) when compared with Group I. The histopathological examination showed an increase in the epithelial proliferation of prostatic cells with involutions protruding into the lumen in BPH group when compared to the normal group. Treatment with Artemisinin (50 mg/kg) reduced the levels of PAP, LDH, prostate weight and prostatic index to a significant extent and restored the histoarchitectural features of the cells. CONCLUSION: The present study concludes that Artemisinin is efficacious in testosterone propionate induced BPH. This could be attributed, at least partly, to its anti-inflammatory property or its role in testosterone level reduction or as a Vitamin D receptor modulator.

Neonatal exposure to androgens dynamically alters gut microbiota architecture.

Gonadal steroids strongly contribute to the metabolic programming that shapes the susceptibility to the manifestation of diseases later in life, and the effect is often sexually dimorphic. Microbiome signatures, together with metabolic traits and sex steroid levels, were analyzed at adulthood in neonatally androgenized female rats, and compared with those of control male and female rats. Exposure of female rats to high doses of androgens on early postnatal life resulted in persistent alterations of the sex steroid profile later on life, namely lower progesterone and higher estradiol and estrone levels, with no effect on endogenous androgens. Neonatally androgenized females were heavier (10% at early adulthood and 26% at adulthood) than controls and had impaired glucose homeostasis observed by higher AUC of glucose in GTT and ITT when subjected to obesogenic manipulations. Androgenized female displayed overt alterations in gut microbiota, indicated especially by higher Bacteroidetes and lower Firmicutes abundance at early adulthood, which disappeared when animals were concurrently overfed at adulthood. Notably, these changes in gut microbiota were related with the intestinal expression of several miRNAs, such as miR-27a-3p, miR-29a-5p, and miR-100-3p. Our results suggest that nutritional and hormonal disruption at early developmental periods not only alters the metabolic programming of the individual later in life but also perturbs the architecture of gut microbiota, which may interact with the host by a cross-talk mediated by intestinal miRNAs; phenomena that may contribute to amplify the metabolic derangement caused by obesity, as seen in neonatally androgenized female rats.

Use of Tregs as a cell-based therapy via CD39 for benign prostate hyperplasia with inflammation.

Benign prostatic hyperplasia (BPH) occurs most commonly among older men, often accompanied by chronic tissue inflammation. Although its aetiology remains unclear, autoimmune dysregulation may contribute to BPH. Regulatory T cells (Tregs) prevent autoimmune responses and maintain immune homeostasis. In this study, we aimed to investigate Tregs frequency, phenotype, and function in BPH patients and to evaluate adoptive transfer Tregs for immunotherapy in mice with BPH via CD39. Prostate specimens and peripheral blood from BPH patients were used to investigate Treg subsets, phenotype and Treg-associated cytokine production. Sorted CD39+/- Tregs from healthy mice were adoptively transferred into mice before or after testosterone propionate administration. The Tregs percentage in peripheral blood from BPH patients was attenuated, exhibiting low Foxp3 and CD39 expression with low levels of serum IL-10, IL-35 and TGF-ß. Immunohistochemistry revealed Foxp3+ cells were significantly diminished in BPH prostate with severe inflammatory. Although the Tregs subset was comprised of more effector/memory Tregs, CD39 was still down-regulated on effector/memory Tregs in BPH patients. Before or after testosterone propionate administration, no alterations of BPH symptoms were observed due to CD39- Tregs in mice, however, CD39+ Tregs existed more potency than Tregs to regulate prostatic hyperplasia and inhibit inflammation by decreasing IL-1ß and PSA secretion, and increasing IL-10 and TGF-ß secretion. Furthermore, adoptive transfer with functional Tregs not only improved prostate hyperplasia but also regulated muscle cell proliferation in bladder. Adoptive transfer with Tregs may provide a novel method for the prevention and treatment of BPH clinically.

Effect of low androgen status on the expression of adenosine A2A and A2B receptors in rat penile corpus cavernosum.

To investigate whether low androgen status affects erectile function by regulating the expression of adenosine A2A and A2B receptors in rat penile corpus cavernosum. Thirty-six 8-week-old male Sprague-Dawley rats were randomly divided into six groups: sham-operated group (4w-sham, 8w-sham), castration group (4w-cast, 8w-cast) and androgen replacement group (4w-cast+T, 8w-cast+T). The rats in the androgen replacement groups were subcutaneously injected with testosterone propionate (3 mg/kg) every other day after castration. The maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP), the expression of A2A , A2B , AKT and eNOS and the concentrations of cAMP and cGMP in the corpus cavernosum were detected at the 4th and 8th weeks after the operation. The serum testosterone level and the ratio of ICPmax/MAP decreased significantly in the castration group as compared to other groups (p < 0.01). There was no significant difference in the expression of A2A receptor among groups, while the expression of A2B , AKT and eNOS and the concentrations of cAMP and cGMP in the castration group were significantly lower than in other groups (p < 0.01). Low androgen status inhibits the AKT/eNOS/cGMP signalling pathways and the production of cAMP in the corpus cavernosum of castrated rats by down-regulating the expression of A2B receptor, and results in decreased of ICPmax/MAP.

Estrogen determines sex differences in adrenergic vessel tone by regulation of endothelial ß-adrenoceptor expression.

Vessels of female rats constrict less and relax more to adrenergic stimulation than vessels of males. Although we have reported that these sex-specific differences rely on endothelial ß-adrenoceptors, the role of sex hormones in ß-adrenoceptor expression and related vessel tone regulation is unknown. We investigated the role of estrogen, progesterone and testosterone on ß-adrenoceptor expression and adrenergic vessel tone regulation, along with sex-specific differences in human mammary arteries. The sex-specific differences in vasoconstriction and vasorelaxation in rat vessels were eliminated after ovariectomy in females. Ovariectomy increased vessel vasoconstriction to norepinephrine more than twofold. Vasorelaxations by isoprenaline and a ß3-agonist were reduced after ovariectomy. Estrogen, but not progesterone substitution, restored sex-specific differences in vasoconstriction and vasorelaxation. Vascular mRNA levels of ß1- and ß3- but not ß2-adrenoreceptors were higher in vessels of females compared with males. Ovariectomy reduced these differences by decreasing ß1- and ß3- but not ß2-adrenoreceptor expression in females. Consistently, estrogen substitution restored ß1- and ß3-adrenoreceptor expression. Orchiectomy or testosterone treatment affected neither vasoconstriction and vasorelaxation nor ß-adrenoceptor expression in vessels of male rats. In human mammary arteries, sex-specific differences in vasoconstriction and vasorelaxation were reduced after removal of endothelium or treatment with l-NMMA. Vessels of women showed higher levels of ß1- and ß3-adrenoceptors than in men. In conclusion, the sex-specific differences in vasoconstriction and vasorelaxation are common for rat and human vessels. In rats, these differences are estrogen but not testosterone or progesterone dependent. Estrogen determines these differences via regulation of vascular endothelial ß1- and ß3-adrenoreceptor expression. NEW & NOTEWORTHY This study proposes a mechanistic concept regulating sex-specific differences in adrenergic vasoconstriction and vasorelaxation. Estrogen increases vascular ß1- and ß3-adrenoceptor expression in female rats. This and our previous studies demonstrate that these receptors are located primarily on endothelium and when activated by norepinephrine act via nitric oxide (NO). Therefore, ß-adrenergic stimulation leads to a more pronounced vasorelaxation in females. Coactivation of endothelial ß1- and ß3-adrenoreceptors leads to higher NO release in vessels of females, ultimately blunting vasoconstriction triggered by activation of smooth muscle α-adrenoceptors.

[The medical aspect of using anabolic androgenic steroids in males attending gyms of Saint-Petersburg].

BACKGROUND: Anabolic androgenic steroids (AASs) are often used by individuals engaged in physical recreational activity. AASs inhibit the hypothalamus-pituitary-gonad axis and can cause erectile dysfunction and reduced fertility. There is no data on the use of AASs in this category of people in the Russian Federation; therefore, a study exploring the rate and patterns of using steroids for non-medical purposes is topical. Aim - of this study was to investigate the rate and patterns of using AASs in males attending gyms in Saint Petersburg. MATERIAL AND METHODS: We used individual anonymous postal survey of males attending gyms. We analyzed demographic and anthropometric data, information on the use of AASs, awareness of their side effects, used agents, patterns and duration of their use, and rehabilitation therapy. RESULTS: Out of 1,815 sent questionnaires, we received back 762 ones. The criteria were met by 550 questionnaires. The mean age was 29.3±7.4 years. The use of AASs was reported by 30.4% of respondents. The main AAS (74.3%) consumers were males aged 22 to 35 years. The most popular drug was Testosterone Propionate (51.5%); the drug was often combined with Oxandrolone (19.7%). In 70.6% of cases, drugs were administered by injection or injection combined with tablet intake. The injectable testosterone dose ranged from 500 to 2,000 mg/week and above. The most common dose was 1,000 mg/week (23.9%). AAS administration for more than 1 year was reported in 16.1% of males. Anastrozole (55%), hCG (51.3%), Clomiphene (41.3%), and Tamoxifen (30.5%) were used during the recovery period. The main source of information on AASs, doses, and dosage patterns was the Internet (48.7%). A negative attitude towards AASs was found in 17.3% of respondents. The desire to receive qualified information about AASs and their impact on health was reported by 54.8% of the surveyed respondents. CONCLUSION: Almost every fourth gym visitor has experience in using AASs. These are males of an optimal reproductive age. The common pattern of using AASs is an aggressive steroid course followed by a recovery period. The list of used drugs and their doses indicate a significant pharmacological intervention and a high risk to health.

"Prostate telocytes change their phenotype in response to castration or testosterone replacement".

Telocytes are CD34-positive cells with a fusiform cell body and long, thin cytoplasmic projections called telopodes. These cells were detected in the stroma of various organs, including the prostate. The prostate is a complex gland capable of undergoing involution due to low testosterone levels; and this condition can be reversed with testosterone replacement. Telocyte function in the mature prostate remains to be dermined, and it is not known whether telocytes can take place in tissue remodeling during prostate involution and regrowth. The present study employed structural, ultrastructural and immunohistochemical methods to investigate the telocyte's phenotypes in the ventral prostate (VP) from control (CT), castrated (CS) and testosterone replacement (TR) groups of adult male Wistar rats. Telocytes were found in the subepithelial, perimuscular and interstitical regions around glandular acini. Telocytes from CT animals have condensed chromatin and long and thin telopodes. In CS group, telocytes appeared quiescent and exhibited layers of folded up telopodes. After TR, telocytes presented loose chromatin, abundant rough endoplasmic reticulum and enlarged telopodes, closely associated with bundles of collagen fibrils. We called these cells "telocytes with a synthetic phenotype". As testosterone levels and glandular morphology returned toward to the CT group parameters, after 10 days of TR, these telocytes progressively switched to the normal phenotype. Our results demonstrate that telocytes exhibit phenotypic plasticity upon androgen manipulation and interact with fibroblast and smooth muscle cells to maintain glandular architecture in control animals and during tissue remodeling after hormonal manipulation.

Endoglin inhibition by sodium acetate and flutamide ameliorates cardiac defective G6PD-dependent antioxidant defense in gestational testosterone-exposed rats.

Gestational androgen excess has been implicated in the development of cardiac dysfunction with poor mechanistic delineation. The role of sodium acetate on cardiac uric acid (UA) production and glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant defense in pregnancy is not known. The study therefore sought to test the hypothesis that rats exposed to elevated testosterone in late pregnancy would have increased cardiac UA production and defective G6PD-dependent antioxidant defense. We also hypothesized that sodium acetate (SAc) or androgen receptor blocker, flutamide (Flu) would ameliorate these effects through endoglin inhibition. Twenty-four pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; po) or Flu (7.5 mg/kg; po) in the late gestation between gestational day 14 and 19. The results showed that in the late gestation, testosterone exposure led to increased plasma and cardiac endoglin. In the heart of rats exposed to gestational testosterone there were elevated lactate dehydrogenase, adenosine deaminase, xanthine oxidase, uric acid (UA), cardiac injury markers and decreased G6PD-dependent antioxidant defense. However, either SAc or Flu comparably ameliorated these testosterone-induced effects. The data from the present study revealed that testosterone exposure in the late gestation causes elevated cardiac Eng that is accompanied by increased UA production and defective G6PD-dependent anti-oxidant defenses. Besides, the findings also suggest that the inhibitory effect of SAc or Flu on endoglin attenuates UA production and enhances the G6PD-dependent anti-oxidant barrier, thereby implying that endoglin may be a potentially novel therapeutic intervention for cardiac dysfunction particularly in pregnancy.

Amelioratory Effects of Testosterone Propionate on Age-related Renal Fibrosis via Suppression of TGF-ß1/Smad Signaling and Activation of Nrf2-ARE Signaling.

Androgen plays a pivotal role in the progression of renal fibrosis. However, whether exogenous androgen treatment to aged male rats can improve the age-related renal fibrosis was not explored. In our study, the changes of morphological structure, renal fibrosis, ultrastructure and renal function, the expressions of extracellular matrix (ECM), matrix metalloproteinases (MMPs) and its tissue inhibitors of metalloproteinases (TIMPs), the expressions of tumor growth factor ß1 (TGF-ß1)/Smad signaling and oxidative stress parameters as well as nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling were tested in kidney of aged male Wistar rats after subcutaneous testosterone propionate (TP, 2 mg/kg/d, 84-day) injection. Aged rats showed significantly renal histopathological changes, increased renal fibrosis, increased thickening of the glomerular basement membrane and the Bowman's capsule basement membrane, declined renal functional, increased ECM, lower expressions of MMP-2 and MMP-9 and higher expressions of TIMP-1 and TIMP-2 in renal tissues and higher expressions of TGF-ß1/Smad signaling, as well as lower expressions of Nrf2-ARE signaling compared to young rats. TP treatment significantly improved age-related above indexes. These results suggested that TP supplement may alleviate age-related renal fibrosis via suppression of TGF-ß1/Smad signaling and activation of Nrf2-ARE signaling in aged rats.

Sex differences in the effect of prenatal testosterone exposure on steroid hormone production in adult rats.

Maternal hyperandrogenism during pregnancy might have metabolic and endocrine consequences on the offspring as shown for the polycystic ovary syndrome. Despite numerous experiments, the impact of prenatal hyperandrogenic environment on postnatal sex steroid milieu is not yet clear. In this study, we investigated the effect of prenatal testosterone excess on postnatal concentrations of luteinizing hormone, corticosterone and steroid hormones including testosterone, pregnenolone, progesterone, estradiol and 7beta-hydroxy-epiandrosterone in the offspring of both sexes. Pregnant rats were injected daily with either testosterone propionate or vehicle from gestational day 14 until parturition. The hormones were evaluated in plasma of the adult offspring. As expected, females had lower testosterone and higher pregnenolone, progesterone and estradiol in comparison to males. In addition, corticosterone was higher in females than in males, and it was further elevated by prenatal testosterone treatment. In males, prenatal testosterone exposure resulted in higher 7beta-hydroxy-epiandrosterone in comparison to control group. None of the other analyzed hormones were affected by prenatal testosterone. In conclusion, our results did not show major effects on sex hormone production or luteinizing hormone release in adult rats resulting from testosterone excess during their fetal development. However, maternal hyperandrogenism seems to partially affect steroid biosynthesis in sex-specific manner.

Hair growth promoting effect of white wax and policosanol from white wax on the mouse model of testosterone-induced hair loss.

White wax (WW) has been traditionally used to treat hair loss in China. However there has been no reporter WW and its extract responsible for hair growth-promoting effect on androgenetic alopecia. In this paper, we examined the hair growth-promoting effects of WW and policosanol of white wax (WWP) on model animal of androgenetic alopecia and the potential target cell of WW and WWP. WW (1, 10 and 20%) and WWP (0.5, 1 and 2%) were applied topically to the backs of mice. Finasteride (2%) was applied topically as a positive control. MTS assays were performed to evaluate cell proliferation in culture human follicle dermal papilla cells (HFDPCs). The inhibition of WW and WWP for 5α- reductase were tested in Vitro. Results showed more lost hairs were clearly seen in mice treated with TP only and TP plus vehicle. Mice which received TP plus WW and WWP showed less hair loss. WW and WWP showed an outstanding hair growth-promoting activity as reflected by the follicular length, follicular density, A/T ratio, and hair bulb diameter. The optimal treatment effect was observed at 10% WW and 1% WWP, which were better than 2% finasteride treatment. MTS assay results suggested that WW and WWP remarkably increased the proliferation of HFDPCs. Inhibitor assay of 5α- reductase showed that WW and WWP inhibited significantly the conversion of testosterone to dihydrotesterone, and the IC50 values of WW and WWP were higher than that of finasteride. In Conclusion, WW and WWP could act against testosterone-induced alopecia in mice, and they promoted hair growth by inhibiting 5α-reductase activity and HFDPCs proliferation. DPCs is the target cell of WW and WWP.

Administration of anabolic steroid during adolescence induces long-term cardiac hypertrophy and increases susceptibility to ischemia/reperfusion injury in adult Wistar rats.

Chronic administration of anabolic androgenic steroids (AAS) in adult rats results in cardiac hypertrophy and increased susceptibility to myocardial ischemia/reperfusion (IR) injury. Molecular analyses demonstrated that hyperactivation of type 1 angiotensin II (AT1) receptor mediates cardiac hypertrophy induced by AAS and also induces down-regulation of myocardial ATP-sensitive potassium channel (KATP), resulting in loss of exercise-induced cardioprotection. Exposure to AAS during adolescence promoted long-term cardiovascular dysfunctions, such as dysautonomia. We tested the hypothesis that chronic AAS exposure in the pre/pubertal phase increases the susceptibility to myocardial ischemia/reperfusion (IR) injury in adult rats. Male Wistar rats (26day old) were treated with vehicle (Control, n=12) or testosterone propionate (TP) (AAS, 5mgkg-1 n=12) 5 times/week during 5 weeks. At the end of AAS exposure, rats underwent 23days of washout period and were submitted to euthanasia. Langendorff-perfused hearts were submitted to IR injury and evaluated for mechanical dysfunctions and infarct size. Molecular analysis was performed by mRNA levels of α-myosin heavy chain (MHC), ßMHC and brain-derived natriuretic peptide (BNP), ryanodine receptor (RyR2) and sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) by quantitative RT-PCR (qRT-PCR). The expression of AT1 receptor and KATP channel subunits (Kir6.1 and SURa) was analyzed by qRT-PCR and Western Blot. NADPH oxidase (Nox)-related reactive oxygen species generation was assessed by spectrofluorimetry. The expression of antioxidant enzymes was measured by qRT-PCR in order to address a potential role of redox unbalance. AAS exposure promoted long-term cardiac hypertrophy characterized by increased expression of ßMHC and ßMHC/αMHC ratio. Baseline derivative of pressure (dP/dt) was impaired by AAS exposure. Postischemic recovery of mechanical properties was impaired (decreased left ventricle [LV] developed pressure and maximal dP/dt; increased LV end-diastolic pressure and minimal dP/dt) and infarct size was larger in the AAS group. Catalase mRNA expression was significantly decreased in the AAS group. In conclusion, chronic administration of AAS during adolescence promoted long-term pathological cardiac hypertrophy and persistent increase in the susceptibility to myocardial IR injury possible due to disturbances on catalase expression.

[Effects of Kudzu Root plus Cinnamon Granules on prostatic hyperplasia in mice].

OBJECTIVE: To explore the effects of Kudzu Root plus Cinnamon Granules (KR+C) on prostatic hyperplasia (PH) in mice. METHODS: Sixty 4-week-old Kunming male mice were randomly divided into six groups: blank control, PH model, high-, medium- and low-dose KR+C, and finasteride control. All the mice except those in the blank control group were subcutaneously injected with testosterone propionate (5 mg / ï¼»kg·dï¼½) at 7 days after surgical castration. The animals of different groups were treated intragastrically with different doses of KR+C, finasteride, and normal saline respectively for 3 weeks and then sacrificed for weighing of the prostate, calculation of the prostatic index, observation of the morphological changes in the prostate after HE staining, determination of the expressions of FGF2, Ki67 and TGF-ß1 by immunohistochemistry, detection of 5α-reductase activity by ELISA, and measurement of the apoptosis index of the prostatic cells by TUNEL. RESULTS: Compared with the model controls, the mice of the other groups showed significantly reduced prostatic volume (P <0.05), prostatic index (P <0.05), expressions of FGF2, Ki67 and TGF-ß1, and activity of 5 α-reductase (P <0.05), but remarkably increased apoptosis index of the prostatic cells (P <0.05). However, no statistically significant differences were observed in the above parameters between the finasteride control and the three KR+C groups (P>0.05). CONCLUSIONS: KR+C can reduce the prostatic volume of PH mice by decreasing the activity of 5α- reductase, inhibiting the expressions of FGF2, Ki67 and TGF-ß1, and promoting the apoptosis of prostatic cells.

[Molecular mechanisms of androgens regulating the eNOS expression in rat corpus cavernosum].

OBJECTIVE: To investigate whether androgens can regulate the expression of eNOS in rat corpus cavernosum through AKT3, PIK3CA, CALM, and CAV1 and influence erectile function. METHODS: Thirty-six 8-week-old male SD rats were randomly divided into groups A (4-week control), B (6-week control), C (4-week castration), D (6-week castration), E (4-week castration + testosterone replacement), and F (6-week castration + testosterone replacement). Both the testis and epididymis were removed from the rats in groups C, D, E and F, and on the second day after surgery, the animals of groups E and F were subcutaneously injected with testosterone propionate at 3 mg per kg of the body weight qd alt while all the others with isodose oil instead. At 4 weeks (for groups A, C and E) and 6 weeks (for groups B, D and F) after treatment, we detected the maximum intracavernous pressure (ICPmax), the mean carotid arterial pressure (MAP) and their ratio (ICPmax/MAP), measured the level of serum testosterone (T), and determined the expressions of eNOS, P-eNOS, AKT3, PIK3CA, CALM and CAV1 in the corpus cavernosum by Western blot and immunohistochemistry. RESULTS: No statistically significant differences were observed in the body weight and MAP among different groups. The serum T level and ICPmax/MAP were remarkably lower in groups C and D than in the other four groups (P<0.01) as well as in groups E and F than in A and B (P<0.05) but exhibited no significant differences either between E and F or between A and B. Immunohistochemistry showed that eNOS and P-eNOS were mainly expressed in the vascular endothelial cell membrane and cavernous vascular lumen, while AKT3, PIK3CA, CALM and CAV1 chiefly in the vascular endothelial cell cytoplasm and membrane, with a few in the smooth muscle cells. Western blot analysis manifested that the expressions of eNOS, P-eNOS, AKT3, PIK3CA, CALM and CAV1 were markedly lower in groups C and D than in A, B, E and F (P<0.01) as well as in D than in C (P<0.05) but those in groups E and F did not showed any significant difference from those in A and B, nor E from F or A from B. CONCLUSIONS: Androgens can improve erectile function by upregulating the expressions of AKT3, PIK3CA, CALM and CAV1 protein molecules and activating eNOS after its phosphorylation, though the exact molecular mechanisms are yet to be further studied.

Efficacy of vaginally applied estrogen, testosterone, or polyacrylic acid on vaginal atrophy: a randomized controlled trial.

OBJECTIVE: Vaginal atrophy is a common chronic condition among postmenopausal women that can affect their quality of life. Recent studies have evaluated new treatment alternatives for vaginal atrophy; however, few therapeutic options have been thoroughly evaluated. This study aimed to compare the effectiveness and adverse effects of estrogen, testosterone, polyacrylic acid, and placebo lubricant for the treatment of postmenopausal women with vaginal atrophy. METHODS: We conducted a randomized clinical trial with 80 postmenopausal women aged between 40 and 70 years who were being followed up at the Menopause Clinic of CAISM UNICAMP between November 2011 and January 2013. Women were randomly assigned to topical vaginal treatment with estrogen, testosterone, polyacrylic acid, and placebo lubricant, three times a week for 12 weeks. We used the vaginal maturation index, pH, vaginal health score, vaginal flora, laboratory tests, and ultrasound to evaluate changes of vaginal atrophy at baseline and after 6 and 12 weeks of treatment. RESULTS: After a 12-week treatment with topical estrogen and testosterone compared with the lubricant, an increased percentage of participants had vaginal pH less than 5, increased vaginal score, and an increase in the number of lactobacilli. Treatment with topical estrogen improved the vaginal maturation index and showed increased levels of estradiol in three women. No changes were observed in the endometrial evaluation of all treatment groups. CONCLUSIONS: After a 12-week treatment with testosterone and estrogen compared with placebo lubrication, there was a significant improvement in vaginal trophism in postmenopausal women with vaginal atrophy.

Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats.

We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 µL); DHT (dihydrotestosterone of 1.0 mg/50 µL); EV (estradiol valerate of 0.1 mg/50 µL); and control (sesame oil of 50 µL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area.