Ultimate Testosterone Stack With  HYPERTEST XTR and MYODEX

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Ultimate Testosterone Stack Stage 1

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Axis Labs Ultimate Testosterone Stack Stage 1

For more advanced testosterone stacks, click here for Stage 2 or Stage 3

Want to experience a smoking hot libido, increased strength, and a muscular physique – without blowing your supplement budget? This is your stack! The Ultimate Testosterone Stack - Stage 1 - offers two of the most powerful testosterone-supporting products you will find anywhere...period. This is the Axis Labs “dynamic duo” of pure testosterone performance. HYPERTEST XTR helps to drive testosterone production and then "free it" for peak bioavailability. Simultaneously, MYODEX promotes testosterone production while helping to buffer DHT and Estrogen - the "spin off" hormones that contribute towards male pattern baldness and fatty deposits in men (like “man boobs”).

Before we can boost testosterone levels, we first must understand what is killing them:

Luteinizing Hormone Disruption, a.k.a hypogonadism

Luteinizing Hormone (LH) is the hormone released by the brain that turns "on" testosterone in the testes like a light switch. Due to aging and lifestyle choices, LH may be disrupted, causing the testes to produce far less testosterone compared to earlier years in life.

Testosterone Neutralized and Rendered Inactive

Sex Hormone-Binding Globulin (SHBG), a glycoprotein, actually serves a good purpose for a while. Similar to a subway car, SHBG transports hormones, like testosterone, throughout the body and regulates their release. Thus, testosterone "on the subway car" is known as "protein-bound" and inactive. Protein-bound testosterone is referred to as Total Testosterone. Once testosterone is released from SHBG, it becomes Free Testosterone, becoming active. Unfortunately, some portion of Total Testosterone stays trapped in the subway car remaining inactive and that portion of the romance-igniting, alpha male hormone cannot do its job.

Usable Testosterone Converting into DHT

Men's bodies produce an enzyme called 5-Alpha Reductase. This enzyme converts testosterone into dihydrotestosterone (DHT). DHT not only robs your body of usable, Free Testosterone, it is the primary cause of male pattern baldness and prostate inflammation, causing a need to urinate more frequently.

Usable Testosterone Converting into Estrogen

An enzyme called Aromatase converts testosterone into a more feminine hormone known as estradiol, the primary estrogen hormone. Elevated estradiol can contribute to the loss of muscle, plummeting sex drive, the creation of more fat stores, and unfortunately may result in the formation of dreaded gynecomastia, also known as "man boobs". The worst part is body fat begets estrogen and estrogen begets body fat - an ugly, vicious cycle.

The Good News! Most of what makes men feel like men requires testosterone. Testosterone regulates sex drive, increases lean body mass, solidifies bone density, boosts energy and contributes to a strong, confident demeanor. When health and confidence is concerned, testosterone is the king of hormones.

Increasing your testosterone levels are achievable safely without steroids (in most cases). To do this, we must first understand why testosterone levels are declining so we can reverse the process.

HYPERTEST XTR™

Addressing Testosterone Killer #1 – Increasing TOTAL Testosterone
Increasing Total Testosterone production from the testes is a result of Luteinizing Hormone (LH) being released from the pituitary gland in the brain. T-SYSTEM™ STEP 1 is a natural nutritional solution formulated to help boost the production of Total Testosterone in the body naturally. In an impressive human clinical study, the primary component in T-SYSTEM STEP 1™ was shown to increase testosterone an average of 46.8% in just 30 days. In this same study, according to the scale used to evaluate the effects of male aging ("AMS") they reported a whopping 60.7% decrease at the conclusion of the study.

Addressing Testosterone Killer #2 – Increasing Free Testosterone
Testosterone must be free to travel into the cell nucleus to turn on the genes necessary for muscle growth, sex drive, etc. T-SYSTEM™ STEP 2 is a precise blend of high quality ingredients to help Free Testosterone to be released from carrier proteins like SHBG.

MYODEX™

Addressing Testosterone Killer #3 – Inhibiting Free Testosterone's Conversion into DHT
Inhibiting Usable Testosterone's Conversion to DHT Enzymes in the body, such as the 5-Alpha Reductase, converts your badly needed, "usable" testosterone into unwanted hormones such as DHT (responsible for hair loss). T-SYSTEM STEP 2™ was formulated to contain ingredients to protect usable testosterone from converting into DHT.

Addressing Testosterone Killer #4 – Inhibiting Estrogen and Conversion
Aromatase enzymes convert excess testosterone into estrogen, resulting in the much-dreaded side effect of gynecomastia (man boobs) and excess accumulation of belly fat. T-SYSTEM STEP 2™ was developed to contain ingredients that help to control estrogen, which would otherwise remain unchecked in the presence of rising natural testosterone.

Bottom line, you owe it to yourself and your loved ones to fight the aging process with a vengeance. A strong, confident and romantic male is not only in your past, but also in your future. Interested in regaining your youthful strength and vitality? Now you know how!

Unleash Your Primal Male Today! Congratulations and Welcome Back to the More Vibrant You!
There's a terrific a - Review by Kayo
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There's a terrific amount of knldoewge in this article! (Posted on 2/7/2017)
Very skeptical - Review by Rick from NY
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A friend of mine told me to order this because he was getting really good results but honestly I thought I would have to go to the real thing to increase testosterone. But I can honestly tell you after about the first week of using the stag I feel more full in the gym and notice more energy at work. Libido is off the charts, if you know what I mean. I would much rather do this then deal with needles and gyno. A am sold. (Posted on 1/4/2017)

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Abdelbaqi, K., N. Lack, et al. "Antiandrogenic and growth inhibitory effects of ring-substituted analogs of 3,3'-diindolylmethane (ring-DIMs) in hormone-responsive LNCaP human prostate cancer cells." Prostate 71(13): 1401-12.

BACKGROUND: Cruciferous vegetables protect against prostate cancer. Indole-3-carbinol (I3C) and its major metabolite 3,3'-diindolylmethane (DIM), exhibit antitumor activities in vitro and in vivo. Several synthetic ring-substituted dihaloDIMs (ring-DIMs) appear to have increased anticancer activity. METHODS: Inhibition of LNCaP prostate cancer cell growth was measured by a WST-1 cell viability assay. Cytoplasmic and nuclear proteins were analyzed by immunoblotting and immunofluorescence. Androgen receptor (AR) activation was assessed by measuring prostate-specific antigen (PSA) expression and using LNCaP cells containing human AR and an AR-dependent probasin promoter-green fluorescent protein (GFP) construct. RESULTS: Like DIM, several ring-substituted dihaloDIM analogs, namely 4,4'-dibromo-, 4,4'-dichloro-, 7,7'-dibromo-, and 7,7'-dichloroDIM, significantly inhibited DHT-stimulated growth of LNCaP cells at concentrations >/=1 microM. We observed structure-dependent differences for the effects of the ring-DIMs on AR expression, nuclear AR accumulation and PSA levels in LNCaP cells after 24 hr. Both 4,4'- and 7,7'-dibromoDIM decreased AR protein and mRNA levels, whereas 4,4'- and 7,7'-dichloroDIM had minimal effect. All four dihaloDIMs (10 and 30 microM) significantly decreased PSA protein and mRNA levels. Immuofluorescence studies showed that only the dibromoDIMs increased nuclear localization of AR. All ring-DIMs caused a concentration-dependent decrease in fluorescence induced by the synthetic androgen R1881 in LNCaP cells transfected with wild-type human AR and an androgen-responsive probasin promoter-GFP gene construct, with potencies up to 10-fold greater than that of DIM. CONCLUSION: The antiandrogenic effects of ring-DIMs suggest they may form the basis for the development of novel agents against hormone-sensitive prostate cancer, alone or in combination with other drugs.

Abel, T., B. Knechtle, et al. (2005). "Influence of chronic supplementation of arginine aspartate in endurance athletes on performance and substrate metabolism - a randomized, double-blind, placebo-controlled study." Int J Sports Med 26(5): 344-9.

The intake of arginine aspartate has been shown to increase anabolic hormones like human growth hormone (hGH) and glucagon. The aim of our study was to investigate whether daily intake of two different dosages of arginine asparate during four weeks affects selected parameters of overtraining syndrome like performance, metabolic and endocrine parameters. Thirty male endurance-trained athletes were included in a randomized, double-blind, placebo-controlled study and divided into three groups. During four weeks, they ingested either arginine aspartate with a high concentration (H) of 5.7 g arginine and 8.7 g aspartate, with a low concentration (L) of 2.8 g arginine and 2.2 g aspartate or placebo (P).VO(2)peak and time to exhaustion were determined on a cycling ergometer in an incremental exercise test before and after supplementation. Before and after each incremental exercise test, concentrations of hGH, glucagon, testosterone, cortisol, ferritine, lactate, and urea were measured. Compared to placebo, no significant differences on endurance performance (VO(2)peak, time to exhaustion), endocrine (concentration of hGH, glucagon, cortisol, and testosterone) and metabolic parameters (concentration of lactate, ferritine, and urea) were found after chronic arginine aspartate supplementation. The chronic intake of arginine asparate during four weeks by male endurance athletes showed independent of dosage no influence on performance, selected metabolic or endocrine parameters. Consequently, there seems to be no apparent reason why the supplementation of arginine aspartate should be an effective ergogenic aid. The practice of using arginine aspartate as potential ergogenics should be critically reevaluated. Further investigations with higher dosage and extended supplementation periods should be performed.

Agrawal, A. K. and B. H. Shapiro (1997). "Gender, age and dose effects of neonatally administered aspartate on the sexually dimorphic plasma growth hormone profiles regulating expression of the rat sex-dependent hepatic CYP isoforms." Drug Metab Dispos 25(11): 1249-56.

Newborn male and female rat pups were injected with either 2 mg or 4 mg monosodium aspartate (MSA)/g body weight or diluent on alternate days for the first 9 days of life. Both doses of the amino acid had profound effects on the sexually dimorphic growth hormone secretory profiles in adulthood. There were no measurable levels of growth hormone in any of the plasma samples obtained during 8 continuous hr of serial blood collections from the adult males and females treated neonatally with 4 mg of MSA. Male rats treated with half the dose of the amino acid (i.e., 2 mg MSA/g) exhibited typical masculine profiles of growth hormone release, except that the amplitudes of the ultradian pulses were reduced to 10-20% of normal male levels. Otherwise, like normal males, the peaks occurred about every 3-4 hr and the intervening 2.5-hr troughs had undetectable levels of growth hormone. In a similar sense, females treated with 2 mg of MSA maintained their sexually dimorphic pattern of plasma growth hormone, i.e., frequent pulses of hormone followed by short-lived troughs. However, the peaks rarely exceeded 20 ng/ml and the troughs usually fell to a measurable 8 to 10 ng/ml resulting in an approximate 75% reduction in the mean plasma concentration. Growth hormone- and gender-dependent expression of CYP2C7, 2C11, 2C12, 2C13, 2A1, 2A2, and 3A2 (mRNAs, proteins, and catalytic activities) were generally unaffected by neonatal exposure to 2 mg of MSA. In contrast, the higher 4-mg dose of the amino acid completely or near completely suppressed male-specific CYP2C11, 2C13, 2A2, and 3A2 expression while inducing small increases in female-specific CYP2C12 and female-predominant CYP2A1 in the treated males. Females exposed to the 4 mg MSA dose exhibited less severe isoform changes characterized by small reductions in CYP2C12 and 2C7 levels. Whereas expression levels of most of the CYP isoforms in both sexes were lowest in the pubertal (47-day-old) rats, and occasionally higher in the adults (207-day-old) as compared with the early postpubertal (70-day-old) rats, the effects of neonatal MSA were the same at all ages studied. Since each of the CYP isoforms are regulated by different "signaling elements" in the sexually dimorphic plasma growth hormone profiles, it is possible to correlate MSA-induced alterations in CYP expression levels to specific changes in the gender-dependent growth hormone profiles.

Ahmad, A., W. A. Sakr, et al. "Novel targets for detection of cancer and their modulation by chemopreventive natural compounds." Front Biosci (Elite Ed) 4: 410-25.

Cancer affects the lives of millions of people. Several signaling pathways have been proposed as therapeutic targets for cancer therapy, and many more continue to be validated. With the identification and validation of therapeutic targets comes the question of designing novel strategies to effectively counter such targets. Natural compounds from dietary sources form the basis of many ancient medicinal systems. They are pleiotropic i.e. they act on multiple targets, and, therefore, are often the first agents to be tested against a novel therapeutic target. This review article summarizes the knowledge so far on some actively pursued targets - Notch, CXCR4, Wnt and sonic hedgehog (shh) pathways, the process of epithelial-mesenchymal transition (EMT) as well as molecular markers such as uPA-uPAR, survivin, FoxM1, and the microRNAs. We have performed an extensive survey of literature to list modulation of these targets by natural agents such as curcumin, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), resveratrol, epigallocatechin-3-gallate (EGCG), genistein etc. We believe that this review will stimulate further research for elucidating and appreciating the value of these wonderful gifts from nature.

Akinbami, M. A., G. H. Philip, et al. (1999). "Expression of mRNA and proteins for testicular steroidogenic enzymes and brain and pituitary mRNA for glutamate receptors in rats exposed to immobilization stress." J Steroid Biochem Mol Biol 70(4-6): 143-9.

The objectives of this study were to determine whether stress attenuates the pituitary LH response to excitatory amino acids by altering expression of glutamate receptor 1 (GluR1) and N-methyl-D-aspartic acid (NMDA) receptor mRNA levels in the hypothalamus or pituitary, and assess whether stress influences testicular levels of mRNA or protein for steroidogenic enzymes. Three hours (h) of immobilization stress was associated with a greater than 7-fold increase in serum corticosterone, and a marked reduction in serum testosterone (T) concentrations. Stress did not significantly alter hypothalamic or pituitary GluR1 and NMDA receptor mRNA levels. Although transcript levels for P450SCC and P45017alpha mRNA in the testis were unchanged in stressed rats, western blotting of testicular fractions revealed reduced amounts of P450SCC and 3beta-HSD, but not P45017alpha. The data suggest that immobilization stress reduces T production by suppressing the translation of transcripts for P450SCC and 3beta-HSD, but the attenuated LH response of stressed animals to NMDA is not mediated by altered hypothalamic or pituitary expression of GluR1 and NMDA receptor levels.

Ali, S., S. Banerjee, et al. "Concurrent inhibition of NF-kappaB, cyclooxygenase-2, and epidermal growth factor receptor leads to greater anti-tumor activity in pancreatic cancer." J Cell Biochem 110(1): 171-81.

Inactivation of survival pathways such as NF-kappaB, cyclooxygenase (COX-2), or epidermal growth factor receptor (EGFR) signaling individually may not be sufficient for the treatment of advanced pancreatic cancer (PC) as suggested by recent clinical trials. 3,3'-Diindolylmethane (B-DIM) is an inhibitor of NF-kappaB and COX-2 and is a well-known chemopreventive agent. We hypothesized that the inhibition of NF-kappaB and COX-2 by B-DIM concurrently with the inhibition of EGFR by erlotinib will potentiate the anti-tumor effects of cytotoxic drug gemcitabine, which has been tested both in vitro and in vivo. Inhibition of viable cells in seven PC cell lines treated with B-DIM, erlotinib, or gemcitabine alone or their combinations was evaluated using 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Significant inhibition in cell viability was observed in PC cells expressing high levels of COX-2, EGFR, and NF-kappaB proteins. The observed inhibition was associated with an increase in apoptosis as assessed by ELISA. A significant down-regulation in the expression of COX-2, NF-kappaB, and EGFR in BxPC-3, COLO-357, and HPAC cells was observed, suggesting that simultaneous targeting of EGFR, NF-kappaB, and COX-2 is more effective than targeting either signaling pathway separately. Our in vitro results were further supported by in vivo studies showing that B-DIM in combination with erlotinib and gemcitabine was significantly more effective than individual agents. Based on our preclinical in vitro and in vivo results, we conclude that this multi-targeted combination could be developed for the treatment of PC patients whose tumors express high levels of COX-2, EGFR, and NF-kappaB.

Allan, C. M., A. Garcia, et al. (2006). "Maintenance of spermatogenesis by the activated human (Asp567Gly) FSH receptor during testicular regression due to hormonal withdrawal." Biol Reprod 74(5): 938-44.

The first activating mutation of the FSH receptor (FSHR*D567G) was identified in a gonadotropin-deficient hypophysectomized man who exhibited persistent spermatogenesis and fertility with only androgen replacement. We have determined the ability of FSHR* activity to maintain spermatogenesis and/or steroidogenesis during gonadotropin and androgen deprivation in mature transgenic FSHR* mice (Tg(Abpa-FSHR*D567G)1Cmal), hereafter referred to as Tg-FSHR* mice. Testes of untreated adult Tg-FSHR* males were equivalent in weight to nontransgenic controls but exhibited increased total Sertoli cell (24%) and spermatogonia (34%) numbers and nonsignificantly elevated spermatocyte-spermatid numbers (13%-17%). During sustained GNRH1 agonist treatment that markedly reduced (96%-98%) serum LH and testosterone (T) and decreased serum FSH (68%-72%), the testes of GNRH1 agonist-treated Tg-FSHR* mice remained significantly larger than treated nontransgenic controls. After 4 wk of gonadotropin suppression, Sertoli cell numbers were reduced in Tg-FSHR* testes to levels comparable with nontransgenic testes, whereas spermatogonia numbers were maintained at higher levels relative to nontransgenic testes. However, after 8 wk of GNRH1 agonist treatment, the total spermatogonia, spermatocyte, or postmeiotic spermatid numbers were reduced to equivalent levels in Tg-FSHR* and nontransgenic mice. FSHR* effects were further examined in gonadotropin-deficient hypogonadal Gnrh1hpg/Gnrh1hpg (Gnrh1(-/-)) mice during testicular regression following withdrawal of T after maximal T-stimulated spermatogenesis. After 6 wk of T withdrawal, spermatogonia, spermatocyte, and postmeiotic spermatid numbers in Tg-FSHR* Gnrh1(-/-) testes decreased to levels found in untreated Tg-FSHR* Gnrh1(-/-) testes. Basal serum T levels in untreated Tg-FSHR* Gnrh1(-/-) males were 2-fold higher than Gnrh1(-/-) controls, but following T treatment/withdrawal, serum T and epididymal weights declined to basal levels found in nontransgenic Gnrh1(-/-) mice. Therefore, FSHR* was unable to sustain circulating T or androgen-dependent epididymal size or postmeiotic spermatogenic development. We conclude that FSHR* activity enhances Sertoli and spermatogenic development in normal testes but has limited ability to maintain spermatogenesis during gonadotropin deficiency, in which the testicular response provided by the FSHR*D567G mutation resembled typical FSH-mediated but not steroidogenic activity.

Angwafor, F., 3rd and M. L. Anderson (2008). "An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males." J Int Soc Sports Nutr 5: 12.

BACKGROUND: Maintaining endogenous testosterone (T) levels as men age may slow the symptoms of sarcopenia, andropause and decline in physical performance. Drugs inhibiting the enzyme 5alpha-reductase (5AR) produce increased blood levels of T and decreased levels of dihydrotestosterone (DHT). However, symptoms of gynecomastia have been reported due to the aromatase (AER) enzyme converting excess T to estradiol (ES). The carotenoid astaxanthin (AX) from Haematococcus pluvialis, Saw Palmetto berry lipid extract (SPLE) from Serenoa repens and the precise combination of these dietary supplements, Alphastat(R) (Mytosterone(trade mark)), have been reported to have inhibitory effects on both 5AR and AER in-vitro. Concomitant regulation of both enzymes in-vivo would cause DHT and ES blood levels to decrease and T levels to increase. The purpose of this clinical study was to determine if patented Alphastat(R) (Mytosterone(trade mark)) could produce these effects in a dose dependent manner. METHODS: To investigate this clinically, 42 healthy males ages 37 to 70 years were divided into two groups of twenty-one and dosed with either 800 mg/day or 2000 mg/day of Alphastat(R) (Mytosterone(trade mark)) for fourteen days. Blood samples were collected on days 0, 3, 7 and 14 and assayed for T, DHT and ES. Body weight and blood pressure data were collected prior to blood collection. One-way, repeated measures analysis of variance (ANOVA-RM) was performed at a significance level of alpha = 0.05 to determine differences from baseline within each group. Two-way analysis of variance (ANOVA-2) was performed after baseline subtraction, at a significance level of alpha = 0.05 to determine differences between dose groups. Results are expressed as means +/- SEM. RESULTS: ANOVA-RM showed significant within group increases in serum total T and significant decreases in serum DHT from baseline in both dose groups at a significance level of alpha = 0.05. Significant decreases in serum ES are reported for the 2000 mg/day dose group and not the 800 mg/day dose group. Significant within group effects were confirmed using ANOVA-2 analyses after baseline subtraction. ANOVA-2 analyses also showed no significant difference between dose groups with regard to the increase of T or the decrease of DHT. It did show a significant dose dependant decrease in serum ES levels. CONCLUSION: Both dose groups showed significant (p = 0.05) increases in T and decreases in DHT within three days of treatment with Alphastat(R) (Mytosterone(trade mark)). Between group statistical analysis showed no significant (p = 0.05) difference, indicating the effect was not dose dependent and that 800 mg/per day is equally effective as 2000 mg/day for increasing T and lowering DHT. Blood levels of ES however, decreased significantly (p = 0.05) in the 2000 mg/day dose group but not in the 800 mg/day dose group indicating a dose dependant decrease in E levels.

Aoki, H., J. Nagao, et al. (2012). "Clinical assessment of a supplement of Pycnogenol(R) and L-arginine in Japanese patients with mild to moderate erectile dysfunction." Phytother Res 26(2): 204-7.

A double-blind parallel group comparison design clinical study was conducted in Japanese patients with mild to moderate erectile dysfunction to investigate the efficacy of a supplement containing Pycnogenol(R) and L-arginine. Subjects were instructed to take a supplement (Pycnogenol(R) 60 mg/day, L-arginine 690 mg/day and aspartic acid 552 mg/day) or an identical placebo for 8 weeks, and the results were assessed using the five-item erectile domain (IIEF-5) of the International Index of Erectile Function. Additionally, blood biochemistry, urinalysis and salivary testosterone were measured. Eight weeks of supplement intake improved the total score of the IIEF-5. In particular, a marked improvement was observed in 'hardness of erection' and 'satisfaction with sexual intercourse'. A decrease in blood pressure, aspartate transaminase and gamma-glutamyl transpeptidase (gamma-GTP), and a slight increase in salivary testosterone were observed in the supplement group. No adverse reactions were observed during the study period. In conclusion, Pycnogenol(R) in combination with L-arginine as a dietary supplement is effective and safe in Japanese patients with mild to moderate erectile dysfunction.

Arslan, M., S. S. Rizvi, et al. (1991). "Possible modulation of N-methyl-D,L-aspartic acid induced prolactin release by testicular steroids in the adult male rhesus monkey." Life Sci 49(15): 1073-7.

N-methyl-D,L-aspartic acid (NMA), an agonist of the neurotransmitter glutamate has been shown to acutely stimulate the release of prolactin (PRL) in intact rats and monkeys. To further investigate the role of neuroexcitatory amino acids in PRL secretion, the effects of NMA administration were examined on PRL release in long term orchidectomized adult rhesus monkeys, in both the absence and presence of testosterone. Intact and long term castrated adult male monkeys weighing between 8-13 kg, were implanted with a catheter via the saphenous vein for blood withdrawal and drug infusion. Blood samples were collected at 10 min intervals for 50 min before and 70 min after administration of the drug or vehicle. Plasma PRL concentrations were estimated using radioimmunoassay. Whereas a single iv injection of NMA (15 mg/kg BW) induced a prompt discharge of PRL in intact monkeys, an identical dose had surprisingly no effect on PRL secretion in orchidectomized animals. On the other hand, plasma PRL increases in response to a challenge dose of thyrotropin releasing hormone (TRH; 6 micrograms/kg BW, iv) were similar in magnitude in the two groups of monkeys. Testosterone replacement in orchidectomized animals by parenteral administration of testosterone enanthate (200 mg/wk) reinitiated the PRL responsiveness to acute NMA stimulation. These results indicate that N-methyl-D-aspartic acid (NMDA) dependent drive to PRL release in the adult male rhesus monkey may be overtly influenced by the sex steroid milieu.

The present study investigated the role of D-aspartic acid (D-Asp) in ovarian steroidogenesis and its effect on aromatase activity in the lizard, Podarcis s. sicula. It was determined that D-Asp concentrations vary significantly during phases of the reproductive cycle: they vary inversely with testosterone concentrations and directly with oestradiol concentrations in the ovary and plasma. Experimental treatment showed that administration of D-Asp induces a decrease in testosterone and an increase in oestradiol, and that treatment with other amino acids (L-Asp, D-Glu and D-Ala) instead of D-Asp has no effects. Experiments in vitro confirmed these results. Furthermore, these experiments showed an increase in aromatase activity, as the addition of D-Asp either to fresh ovarian tissue homogenate or to acetonic powder of ovarian follicles induced a significant increase in the conversion of testosterone to oestradiol. Aromatase activity is four times greater in the presence of D-Asp than in its absence. However, almost equivalent values of the two K(m) values (both approximately 25 nmol l(-1)) indicate that aromatase has the same catalytic properties in both cases.

Berges, R. R., J. Windeler, et al. (1995). "Randomised, placebo-controlled, double-blind clinical trial of beta-sitosterol in patients with benign prostatic hyperplasia. Beta-sitosterol Study Group." Lancet 345(8964): 1529-32.

Medical treatments have become available for benign hypertrophy of the prostate, including alpha-receptor blocking agents and 5-alpha-reductase inhibitors. Drugs derived from plants, for which no precise mechanism of action has been described, are widely used for this purpose in Europe. In a randomised, double-blind, placebo-controlled multicentre study, 200 patients (recruited between April and October 1993) with symptomatic benign prostatic hyperplasia were treated with either 20 mg beta-sitosterol (which contains a mixture of phytosterols) three times per day or placebo. Primary end-point was a difference of modified Boyarsky score between treatment groups after 6 months; secondary end-points were changes in International Prostate Symptom Score (IPSS), urine flow, and prostate volume. Modified Boyarsky score decreased significantly with a mean of -6.7 (SD 4.0) points in the beta-sitosterol-treated group versus -2.1 (3.2) points in the placebo group p < 0.01. There was a decrease in IPSS (-7.4 [3.8] points in the beta-sitosterol-treated group vs -2.1 [3.8] points in the placebo group) and changes in urine flow parameters: beta-sitosterol treatment resulted in increasing peak flow (15.2 [5.7] mL/s from 9.9 [2.5] mL/s), and decrease of mean residual urinary volume (30.4 [39.9] mL from 65.8 [20.8] mL). These parameters did not change in the placebo group (p < 0.01). No relevant reduction of prostatic volume was observed in either group. Significant improvement in symptoms and urinary flow parameters show the effectiveness of beta-sitosterol in the treatment of benign prostatic hyperplasia.

Boberg, K. M., E. Lund, et al. (1990). "Formation of C21 bile acids from plant sterols in the rat." J Biol Chem 265(14): 7967-75.

Formation of bile acids from sitosterol in bile-fistulated female Wistar rats was studied with use of 4-14C-labeled sitosterol and sitosterol labeled with 3H in specific positions. The major part (about 75%) of the 14C radioactivity recovered as bile acids in bile after intravenous administration of [4-14C]sitosterol was found to be considerably more polar than cholic acid, and only trace amounts of radioactivity had chromatographic properties similar to those of cholic acid and chenodeoxycholic acid. It was shown that polar metabolites were formed by intermediate oxidation of the 3 beta-hydroxyl group (loss of 3H from 3 alpha-3H-labeled sitosterol) and that the most polar fraction did not contain a hydroxyl group at C7 (retention of 3H in 7 alpha,7 beta-3H2-labeled sitosterol). Furthermore, the polar metabolites had lost at least the terminal 6 or 7 carbon atoms of the side chain (loss of 3H from 22,23-3H2- and 24,28-3H2-labeled sitosterol). Experiments with 3H-labeled 7 alpha-hydroxysitosterol and 4-14C-labeled 26-hydroxysitosterol showed that none of these compounds was an efficient precursor to the polar metabolites. By analysis of purified most polar products of [4-14C] sitosterol by radio-gas chromatography and the same products of 7 alpha,7 beta-[2H2]sitosterol by combined gas chromatography-mass spectrometry, two major metabolites could be identified as C21 bile acids. One metabolite had three hydroxyl groups (3 alpha, 15, and unknown), and one had two hydroxyl groups (3 alpha, 15) and one keto group. Considerably less C21 bile acids were formed from [4-14C]sitosterol in male than in female Wistar rats. The C21 bile acids formed in male rats did not contain a 15-hydroxyl group. Conversion of a [4-14C]sitosterol into C21 bile acids did also occur in adrenalectomized and ovariectomized rats, indicating that endocrine tissues are not involved. Experiments with isolated perfused liver gave direct evidence that the overall conversion of sitosterol into C21 bile acids occurs in this organ. Intravenously injected 7 alpha,7 beta-3H-labeled campesterol gave a product pattern identical to that of 4-14C-labeled sitosterol. Possible mechanisms for hepatic conversion of sitosterol and campesterol into C21 bile acids are discussed.

Borowicz, K. K. (2001). "Effect of antihormones in amygdala-kindled seizures in rats." Pol J Pharmacol 53(1): 61-3.

Tamoxifen (TXF; an antiestrogen), cyproterone acetate (CYP; an antiandrogen) and mifepristone (MIF; an antigestagen) did not affect kindling parameters (afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration) in fully-kindled rats. TXF (50 mg/kg) and CYP (50 mg/kg), when combined with carbamazepine, or phenobarbital, both antiepileptics administered at their highest subprotective doses of 15 mg/kg, resulted in significant reduction of the seizure and afterdischarge durations, both in male and female rats. Additionally, the combination of carbamazepine and cyproterone markedly increased the afterdischarge threshold in fully-kindled rats of both genders. The interaction between antihormones and carbamazepine, or phenobarbital, was not reversed by the respective gonadal hormones (estradiol, progesterone, and testosterone), kainic acid, or strychnine. However, the TXF-, and CYP-induced effect on the action of carbamazepine was abolished by bicuculline, N-methyl-D-aspartic acid and aminophylline. The effect of TXF on the protective activity of phenobarbital was reversed by bicuculline and N-methyl-D-aspartic acid. Finally, the CYP-mediated effect on phenobarbital action was abolished by bicuculline and aminophylline. Neither TXF nor CYP altered free plasma levels and brain levels of carbamazepine or phenobarbital, so a pharmacokinetic interaction between antihormones and antiepileptic drugs is not probable. In view of the present data, it may be suggested that the protective activity of the antiestrogen and antiandrogen are mostly associated with the enhancement of GABA-ergic and purinergic transmission in the central nervous system. Also the augmentation of glutamatergic transmission, realized through NMDA receptors, may be involved in the mechanism of antiseizure action of TXF and CYP.

Borowicz, K. K., J. Luszczki, et al. (2002). "Effects of tamoxifen, mifepristone and cyproterone on the electroconvulsive threshold and pentetrazole-induced convulsions in mice." Pol J Pharmacol 54(2): 103-9.

The aim of this study was to evaluate the efficacy of three antihormones, tamoxifen (TXF, an antiestrogen), mifepristone (MIF, an antiprogesterone) and cyproterone (CYP, an antiandrogen) in two major models of experimental epilepsy, electrically and pentetrazole (PTZ)-evoked seizures in mice. TXF (20-50 mg/kg) significantly raised the threshold for electroconvulsions in female mice, whereas CYP was active in male mice. Similar effects were observed in castrated mice. Different data were obtained in sexually immature animals since both TXF and CYP exerted anticonvulsive effects in animals of both genders. MIF (5-50 mg/kg) remained without effect on electrically evoked seizures in mice. The anticonvulsive action of TXF was reversed by aminophylline, bicuculline, kainic acid and N-methyl-D-aspartic acid, but not by estradiol or strychnine. The protective action of CYP was reversed by aminophylline and bicuculline, but not by testosterone, kainic acid, N-methyl-D-aspartic acid or strychnine. All three antihormones were ineffective against PTZ-induced convulsions in mice. Our results suggest that the action of TXF and CYP might be indirectly associated with the respective hormonal receptor-mediated events, but the nature of this dependence is unclear and further investigations are needed to elucidate this phenomenon.

Borowicz, K. K., J. Luszczki, et al. (2004). "Influence of sexual hormone antagonists on the anticonvulsant action of conventional antiepileptic drugs against electrically- and pentylenetetrazol-induced seizures in mice." Eur Neuropsychopharmacol 14(1): 77-85.

The present results refer to the action of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) on seizure phenomena in mice. TXF and CYP at their lowest protective dose in the electroconvulsive threshold test, enhanced the antiseizure efficacy of some antiepileptic drugs. TXF (20 mg/kg) potentiated the protective activity of valproate, diphenylhydantoin and clonazepam, but not that of carbamazepine or phenobarbital, against maximal electroshock-induced convulsions in female mice. CYP (40 mg/kg) enhanced the anticonvulsant action of valproate, carbamazepine, diphenylhydantoin and clonazepam, but not that of phenobarbital, against maximal electroshock in male animals. MIF failed to affect the electroconvulsive threshold or the efficacy of antiepileptic drugs in maximal electroshock. The effect of TXF or CYP upon the electroconvulsive threshold and on the action of antiepileptics was not reversed by sex steroid hormones (estradiol, testosterone, progesterone). However, the TXF-induced elevation of the electroconvulsive threshold was abolished by bicuculline, N-methyl-D-aspartic acid and kainic acid, and partially reversed by aminophylline, strychnine being ineffective in this respect. The action of CYP on the threshold for electroconvulsions was partially reversed by bicuculline and aminophylline. Both glutamatergic agonists and strychnine remained ineffective in this respect. Moreover, the action of TXF or CYP on the activity of antiepileptics was not influenced by strychnine, and reversed to various extents by the remaining convulsants. In contrast to maximal electroshock, none of the three antihormones affected the protective action of antiepileptic drugs against pentylenetetrazol-induced seizures in mice. Neither TXF nor CYP altered the free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs, providing 50% protection against maximal electroshock, did not affect motor performance in mice, and did not result in significant long-term memory deficits. Our data indicate that steroid receptor-mediated events may be indirectly associated with seizure phenomena in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.

Brown, G. A., M. D. Vukovich, et al. (2000). "Effects of anabolic precursors on serum testosterone concentrations and adaptations to resistance training in young men." Int J Sport Nutr Exerc Metab 10(3): 340-59.

The effects of androgen precursors, combined with herbal extracts designed to enhance testosterone formation and reduce conversion of androgens to estrogens was studied in young men. Subjects performed 3 days of resistance training per week for 8 weeks. Each day during Weeks 1, 2, 4, 5, 7, and 8, subjects consumed either placebo (PL; n = 10) or a supplement (ANDRO-6; n = 10), which contained daily doses of 300 mg androstenedione, 150 mg DHEA, 750 mg Tribulus terrestris, 625 mg Chrysin, 300 mg Indole-3-carbinol, and 540 mg Saw palmetto. Serum androstenedione concentrations were higher in ANDRO-6 after 2, 5, and 8 weeks (p <.05), while="" serum="" concentrations="" of="" free="" and="" total="" testosterone="" were="" unchanged="" in="" both="" groups="" estradiol="" was="" elevated="" at="" weeks="" 2="" 5="" 8="" andro-6="" p="" 05="" estrone="" muscle="" strength="" increased="" similarly="" from="" 0="" to="" 4="" again="" treatment="" the="" acute="" effect="" one="" third="" daily="" dose="" pl="" studied="" 10="" men="" 23="" -="" years="" androstenedione="" 150="" 360="" min="" after="" ingestion="" or="" these="" data="" provide="" evidence="" that="" addition="" herbal="" extracts="" does="" not="" result="" reduce="" estrogenic="" augment="" adaptations="" resistance="" training="" blockquote="">

Burrone, L., F. Raucci, et al. (2012). "Steroidogenic gene expression following D-aspartate treatment in frog testis." Gen Comp Endocrinol 175(1): 109-17.

Previous studies have provided evidence that D-Asp plays a role in steroid-mediated reproductive biology in amphibians, reptiles, birds and mammals. To examine the molecular involvement of D-Asp on steroidogenic pathway regulation, we analysed the expression of StAR, P450 aromatase and 5alphaRed2 mRNAs in Pelophylax esculentus testis, either in relation to the reproductive cycle or D-Asp treatment. Basal StAR mRNA levels, as well as D-Asp and testosterone concentrations, were higher in reproductive than in post-reproductive frogs. D-Asp treatment increased StAR mRNA expression and immunolocalisation in both the reproductive and post-reproductive periods. In control testis, aromatase mRNA levels were higher in the post-reproductive period, but following D-Asp administration, they increased only in the reproductive period. The level of 5alphaRed2 mRNA was higher in reproductive frogs than in post-reproductive frogs, and it increased after D-Asp treatment only in the post-reproductive phase. Our results suggest that, in P. esculentus testis, D-Asp increases StAR mRNA in both periods, and P450 aromatase and 5alphaRed2 mRNAs at different points during the reproductive cycle.

Burrone, L., A. Santillo, et al. (2012). "Induced synthesis of P450 aromatase and 17beta-estradiol by D-aspartate in frog brain." J Exp Biol 215(Pt 20): 3559-65.

d-Aspartic acid is an endogenous amino acid occurring in the endocrine glands as well as in the nervous system of various animal phyla. Our previous studies have provided evidence that d-aspartate plays a role in the induction of estradiol synthesis in gonads. Recently, we have also demonstrated that d-aspartic acid induces P450 aromatase mRNA expression in the frog (Pelophylax esculentus) testis. P450 aromatase is the key enzyme in the estrogen synthetic pathway and irreversibly converts testosterone into 17beta-estradiol. In this study, we firstly investigated the immunolocalisation of P450 aromatase in the brain of P. esculentus, which has never previously been described in amphibians. Therefore, to test the hypothesis that d-aspartate mediates a local synthesis of P450 aromatase in the frog brain, we administered d-aspartate in vivo to male frogs and then assessed brain aromatase expression, sex hormone levels and sex hormone receptor expression. We found that d-aspartate enhances brain aromatase expression (mRNA and protein) through the CREB pathway. Then, P450 aromatase induces 17beta-estradiol production from testosterone, with a consequent increase of its receptor. Therefore, the regulation of d-aspartate-mediated P450 aromatase expression could be an important step in the control of neuroendocrine regulation of the reproductive axis. Accordingly, we found that the sites of P450 aromatase immunoreactivity in the frog brain correspond to the areas known to be involved in neurosteroid synthesis.

Cabeza, M., E. Bratoeff, et al. (2003). "Effect of beta-sitosterol as inhibitor of 5 alpha-reductase in hamster prostate." Proc West Pharmacol Soc 46: 153-5.

Canivenc-Lavier, M. C., M. F. Vernevaut, et al. (1996). "Comparative effects of flavonoids and model inducers on drug-metabolizing enzymes in rat liver." Toxicology 114(1): 19-27.

The inducing effects of some flavonoids (flavone, flavanone, tangeretin and quercetin) and model substances have been studied in rats, and the activity and the expression of drug-metabolizing enzymes have been compared in rats. The addition of flavonoids to the diet (0.3% w/w) for 2 weeks did not change the liver cytochrome P450 content nor the activities of the NADPH-cytochrome P450 and NADH-cytochrome b5 reductases, but it affected the activities of phase I and phase II enzymes. Flavone, and to a lesser extent tangeretin, increased the activities mediated by the P450 1A1,2 (EROD) and 2B1,2 (PROD) as well as the activities of p-nitrophenol UDP-glucuronyl transferase (UGT) and glutathione transferase (GST). Flavanone mainly enhanced PROD, UGT and GST, whereas quercetin did not modify any enzyme activities. None of the tested flavonoids modulated the activities catalyzed by P450 2E1, 3A and 4A. Immunoblotting studies showed that flavone and tangeretin increased the expression of cytochrome P450 1A and 2B forms, whereas flavanone only induced cytochrome P450 2B. Flavone and to a lesser extent flavanone, markedly increased the phenol-UGT protein level. Both flavone and flavanone also increased the androsterone- and testosterone-UGTs, whereas tangeretin and quercetin did not increase any UGT isoform. We concluded that the flavonoids tested specifically affected the expression of the drug-metabolizing isozymes in rat liver, their inducing properties were dependent on their chemical structures.

Canto, P., D. Soderlund, et al. (2002). "Mutational analysis of the luteinizing hormone receptor gene in two individuals with Leydig cell tumors." Am J Med Genet 108(2): 148-52.

Inactivating mutations of the luteinizing hormone receptor (LHR) gene in males induce Leydig cell agenesis or hypoplasia, while activating mutations cause testotoxicosis. Recently, it was demonstrated that a somatic heterozygous activating mutation of the LHR gene (Asp578His), limited to the tumor, was the cause of Leydig cell adenomas in three unrelated patients. We describe the molecular study of two unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas. Genomic DNA was extracted from the tumor, the adjacent normal testis tissue, and blood leukocytes. Both individuals exhibited an heterozygous missense mutation, limited only to the tumor, consisting of a guanine (G) to cytosine (C) substitution at codon 578 (GAT to CAT), turning aspartic acid into histidine. The presence of the same mutation in different ethnic groups demonstrates the existence of a mutational hot spot in the LHR gene. Indeed, this mutation occurs at the conserved aspartic acid residue at amino acid 578, where a substitution by glycine is the most common mutation observed in testotoxicosis and where a substitution by tyrosine has been linked to a more severe clinical phenotype where diffuse Leydig cell hyperplasia is found. Our results confirm the fact that somatic activating mutations of gonadotropin receptors are involved in gonadal tumorigenesis.

Castell, L. M., L. M. Burke, et al. (2009). "BJSM reviews: A-Z of supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance Part 2." Br J Sports Med 43(11): 807-10.

Cho, H. J., S. Y. Park, et al. "3,3'-Diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model." Mol Carcinog 50(2): 100-12.

3,3'-Diindolylmethane (DIM) is a major in vivo derivative of indole-3-carbinol, which is present in cruciferous vegetables and has been reported to possess anti-carcinogenic properties. In the present study, we examined whether DIM inhibits the development of prostate cancer using the transgenic adenocarcinoma mouse prostate (TRAMP) model. DIM feeding inhibited prostate carcinogenesis in TRAMP mice, reduced the number of cells expressing the SV40 large tumor antigen and proliferating cell nuclear antigen, and increased the number of terminal dUTP nick-end labeling-positive cells in the dorsolateral lobes of the prostate. Additionally, DIM feeding reduced the expression of cyclin A, cyclin-dependent kinase (CDK)2, CDK4, and Bcl-xL, and increased p27 and Bax expression. To assess the mechanisms by which DIM induces apoptosis, LNCaP and DU145 human prostate cancer cells were cultured with various concentrations of DIM. DIM induced a substantial reduction in the numbers of viable cells and induced apoptosis in LNCaP and DU145 cells. DIM increased the cleavage of caspase-9, -7, -3, and poly (ADP-ribose) polymerase (PARP). DIM increased mitochondrial membrane permeability and the translocation of cytochrome c and Smac/Diablo from the mitochondria. Additionally, DIM induced increases in the levels of cleaved caspase-8, truncated Bid, Fas, and Fas ligand, and the caspase-8 inhibitor Z-IETD-FMK was shown to mitigate DIM-induced apoptosis and the cleavage of caspase-3, PARP, and Bid. These results indicate that DIM inhibits prostate carcinogenesis via induction of apoptosis and inhibition of cell cycle progression. DIM induces apoptosis in prostate cancer cells via the mitochondria- and death receptor-mediated pathways.

Costello, L. C., V. Akuffo, et al. (1988). "Testosterone stimulates net citrate production from aspartate by prostate epithelial cells." Horm Metab Res 20(4): 252-3.

Cousin, P., L. Calemard-Michel, et al. (2004). "Influence of SHBG gene pentanucleotide TAAAA repeat and D327N polymorphism on serum sex hormone-binding globulin concentration in hirsute women." J Clin Endocrinol Metab 89(2): 917-24.

SHBG is the specific plasma transport protein for sex steroid hormones in humans. Plasma SHBG concentration follows a gender dimorphism but varies with nutritional and hormonal status in both sexes. In addition, a genetic influence on SHBG in humans has recently been suggested by family studies. We investigated the relationship between a point mutation (D327N) in SHBG gene exon 8 that delays human SHBG half-life and a pentanucleotide repeat polymorphism [PNRP (TAAAA)(n)] in the SHBG gene 5' untranslated region that influences transcription in vitro, on the one hand, and SHBG levels on the other, in a population of 303 women referred for hirsutism. Of these patients, 154 (51%) met the criteria for polycystic ovary syndrome (PCOS) and 124 (41%) were overweight [body mass index (BMI) > or = 25 kg/m(2)]. The two SHBG gene alleles for D327N substitution, wild-type (W) and variant (v), were identified by restriction fragment length polymorphism in the whole population, and the GeneScan method was used to identify PNRP alleles in 245 subjects. Six alleles of the pentanucleotide motif with six to 11 repeats were present in our population. Plasma SHBG concentration was related to PCOS status, non-SHBG-bound testosterone, BMI, fasting blood glucose level, fasting insulinemia, and D327N allele v. The v allele was associated with higher SHBG levels [36.9 +/- 15.9 nmol/liter for W/v (n = 52) and 43.5 +/- 3.5 nmol/liter for v/v (n = 2)] than was the wild-type W allele [31.1 +/- 16.1 nmol/liter (n = 249); P = 0.039]. Multivariate analysis showed that BMI, PCOS status, and D327N polymorphism influenced plasma SHBG concentrations, each of these parameters contributing independently of the others. Investigating the role of each allele of the TAAAA repeat polymorphism on SHBG levels was more complex because of the number of different genotypes (as many as 18 in our population) and the low frequency of some of them. Moreover, a strong disequilibrium linkage was found between D327N allele v and the eight-TAAAA repeat allele (P < 0.0001). This could mask the effect of the TAAAA repeat polymorphism on SHBG concentration in vivo. Nevertheless, SHBG levels in patients who were homozygous for six repeats (34.9 +/- 16.2 nmol/liter; n = 21) were significantly (P = 0.043) higher than in nine-repeat homozygous patients (21.5 +/- 13.0 nmol/liter; n = 8), and lay between the two for eight-repeat homozygous patients (28.5 +/- 15.8 nmol/liter; n = 44). Delineating the precise role of this PNRP polymorphism will need further investigation in a large healthy population. In summary, although BMI and PCOS status have a major influence on circulating SHBG levels in hirsute women, the present results support the notion that polymorphism(s) within the coding sequence and, potentially, in the regulatory sequence of the SHBG gene are associated with circulating SHBG levels and may represent part of the genetic background of sex steroid hormone activity in humans.

Czlonkowska, A. I., P. Krzascik, et al. (2000). "The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol." Pharmacol Biochem Behav 67(2): 345-53.

The effects of intraperitoneally (IP) or intracerebroventricularly (ICV) administered neurosteroids [allopregnanolone (AP); 5beta-tetrahydrodeoxycorticosterone (5beta-THDOC); dehydroepiandrosterone sulfate (DHEAS); pregnenolone sulfate (PS)] and their precursors [progesterone (PROG), pregnanedione (PREG)] on N-methyl-D-aspartic acid (NMDA)-, picrotoxin (PTX)- and bicuculline (BIC)-induced seizures and ethanol-induced sleep were studied in mice. It was found that IP injections of (+)MK-801 most potently antagonized NMDA-, PTX- and BIC-induced seizures, as compared to diazepam (DZP), PROG and PREG. Both precursors of neurosteroids appeared only marginally active in the applied models of convulsions. ICV injections of AP selectively blocked PTX- and BIC-induced seizures, whereas 5beta-THDOC and (+)MK-801 also antagonized NMDA-induced convulsions. ICV administered DHEAS induced seizures in a dose-dependent way. ICV injections of AP and midazolam shortened the latency and prolonged the duration of sleep induced by IP injections of ethanol (5.0 g/kg). On the contrary, DHEAS and PS significantly reduced the hypnotic-like effect of ethanol. The obtained results suggest that neurosteroids may modulate in an agonistic (AP, 5beta-THDOC), or antagonistic way (PS, DHEAS), the GABA(A) receptor complex functions. Some of them (5beta-THDOC) also interact with NMDA receptors. AP appeared to be the most selectively acting compound, with its profile of action fully comparable to that of midazolam. AP also enhanced the hypnotic effect of ethanol, pointing out to the propensity to interact with centrally depressant agents. These findings, together with the possibility of conversion of some neurosteroids in the brain to other steroid hormones (testosterone, estradiol and aldosterone), indicate the limitations of their use for the treatment of neurological and psychiatric disorders.

Damian, E., O. Ianas, et al. (1980). "Purification and characterization of the antigonadotropic pineal substance." Endocrinologie 18(2): 79-84.

Purification by ultrafiltration of the melatonin-free pineal extract proved to have an antigonadotropic activity enabled the authors to obtain two fractions: one with a molecular weight above 10,000 and a second one with a molecular weight under 10,000 daltons. A biologic trial made by applying the mouse uterus weight test showed that both fractions inhibited the stimulating effect of exogenous HCG on the uterus. Ventral prostate weight test applied to rats showed that only the fraction above 10,000 daltons lowered the weight of this organ under basal conditions and that it inhibited the stimulating effect of exogenous testosterone on the prostate. The fraction with a molecular weight above 10,000 daltons contains 76% Lowry proteins from the total pineal extract and 4% aminic nitrogen and in the polyacrylamide gel electrophoresis it appears as two protein bands. The fraction with a molecular weight under 10,000 daltons contains only 20% proteins and 26% aminic nitrogen from the total pineal extract. Paper chromatography of the amino acids has shown that the lower molecular weight fraction does not contain proline, tyrosine, arginine, lysine and histidine and that in both fractions prevail the aspartic and glutamic acids.

D'Aniello, A. (2007). "D-Aspartic acid: an endogenous amino acid with an important neuroendocrine role." Brain Res Rev 53(2): 215-34.

D-Aspartic acid (d-Asp), an endogenous amino acid present in vertebrates and invertebrates, plays an important role in the neuroendocrine system, as well as in the development of the nervous system. During the embryonic stage of birds and the early postnatal life of mammals, a transient high concentration of d-Asp takes place in the brain and in the retina. d-Asp also acts as a neurotransmitter/neuromodulator. Indeed, this amino acid has been detected in synaptosomes and in synaptic vesicles, where it is released after chemical (K(+) ion, ionomycin) or electric stimuli. Furthermore, d-Asp increases cAMP in neuronal cells and is transported from the synaptic clefts to presynaptic nerve cells through a specific transporter. In the endocrine system, instead, d-Asp is involved in the regulation of hormone synthesis and release. For example, in the rat hypothalamus, it enhances gonadotropin-releasing hormone (GnRH) release and induces oxytocin and vasopressin mRNA synthesis. In the pituitary gland, it stimulates the secretion of the following hormones: prolactin (PRL), luteinizing hormone (LH), and growth hormone (GH) In the testes, it is present in Leydig cells and is involved in testosterone and progesterone release. Thus, a hypothalamus-pituitary-gonads pathway, in which d-Asp is involved, has been formulated. In conclusion, the present work is a summary of previous and current research done on the role of d-Asp in the nervous and endocrine systems of invertebrates and vertebrates, including mammals.

D'Aniello, A., A. Di Cosmo, et al. (1996). "Involvement of D-aspartic acid in the synthesis of testosterone in rat testes." Life Sci 59(2): 97-104.

D-Aspartic acid (D-Asp) is an endogenous amino acid which occurs in many marine and terrestrial animals. In fetal and young rats, this amino acid occurs prevalently in nervous tissue, whereas at sexual maturity it occurs in endocrine glands and above all in pituitary and testes. Here, we have studied if a relationship exists between the presence of D-Asp and the hormonal activity. The following results were obtained: 1) Both D-Asp and testosterone are synthesized in rat testes in two periods of the animal's life: before birth, about the 17th day after fertilization and, after birth, at sexual maturity. 2) Immunocytochemical studies have demonstrated that this enantiomer is localized in Leydig and Sertoli cells. 3) In vivo experiments, consisting of i.p. injection of D-Asp to adult male rats, demonstrated that this amino acid accumulates in pituitary and testis (after 5 h, the accumulation was of 12 and 4-fold over basal values, respectively); simultaneously, luteinizing hormone, testosterone and progesterone significantly increased in the blood (1.6-fold, p < 0.05; 3.0-fold, p < 0.01 and 2.9-fold, p < 0.01, respectively). 4) Finally, in vitro experiments, consisting of the incubation of D-Asp with isolated testes also demonstrated that this amino acid induces the synthesis of testosterone. These results suggest that free D-Asp is involved in the steroidogenesis.

D'Aniello, A., M. M. Di Fiore, et al. (1998). "Secretion of D-aspartic acid by the rat testis and its role in endocrinology of the testis and spermatogenesis." FEBS Lett 436(1): 23-7.

The D-isomer of aspartic acid (D-Asp) has been found in rat testes. In the present study, samples of testicular venous blood plasma, rete testis fluid, interstitial extracellular fluid, luminal fluid from the seminiferous tubules, testicular parenchymal cells, epididymal spermatozoa and peripheral blood plasma were collected and analyzed for D-Asp by two methods, an enzymatic and a chromatographic HPLC method. The two methods gave very similar results for all samples. The highest concentrations of D-Asp (about 120 nmol/ml) were found in testicular venous blood plasma, with slightly lower concentrations in rete testis fluid (95 nmol/ml) and epididymal spermatozoa (80 nmol/g wet weight). Lower levels were found in testicular parenchymal cells (which would comprise mostly spermatids and spermatocytes), luminal fluid from the seminiferous tubules and interstitial extracellular fluid (26, 23 and 11 nmol/ml respectively). However, these values were all higher than those for peripheral blood plasma (6 nmol/ml). It would appear that D-Asp is being secreted by the testis mostly into the venous blood, passing thence into the rete testis fluid and being incorporated into the spermatozoa at the time or after they leave the testis. The distribution of D-Asp is thus quite different from that of testosterone, and its role and the reason for its high concentration in the male reproductive tract remain to be elucidated.

D'Aniello, A., P. Spinelli, et al. (2003). "Occurrence and neuroendocrine role of D-aspartic acid and N-methyl-D-aspartic acid in Ciona intestinalis." FEBS Lett 552(2-3): 193-8.

Probes for the occurrence of endogenous D-aspartic acid (D-Asp) and N-methyl-D-aspartic acid (NMDA) in the neural complex and gonads of a protochordate, the ascidian Ciona intestinalis, have confirmed the presence of these two excitatory amino acids and their involvement in hormonal activity. A hormonal pathway similar to that which occurs in vertebrates has been discovered. In the cerebral ganglion D-Asp is synthesized from L-Asp by an aspartate racemase. Then, D-Asp is transferred through the blood stream into the neural gland where it gives rise to NMDA by means of an NMDA synthase. NMDA, in turn, passes from the neuronal gland into the gonads where it induces the synthesis and release of a gonadotropin-releasing hormone (GnRH). The GnRH in turn modulates the release and synthesis of testosterone and progesterone in the gonads, which are implicated in reproduction.

Davis, A. M., S. C. Ward, et al. (1999). "Developmental sex differences in amino acid neurotransmitter levels in hypothalamic and limbic areas of rat brain." Neuroscience 90(4): 1471-82.

GABA, glutamate and aspartate are the predominant amino acid neurotransmitters in the mammalian brain. We have previously reported a developmental sex difference in messenger RNA levels of glutamate decarboxylase, the rate-limiting enzyme in GABA synthesis [Davis A. M. et al. (1996) Horm. Behav. 30, 538-552]. Males were found to have significantly higher levels of messenger RNA in many steroid-concentrating regions of the hypothalamus and limbic system on day 1 of life. Therefore, in this study, we have examined levels of amino acid neurotransmitters during early postnatal development in many of the same or related brain areas. We found that levels of all three transmitters change as animals age. While both GABA and aspartate concentrations increase, glutamate levels decrease. In addition, there are sex differences in neurotransmitter levels in several areas examined, including the ventromedial and arcuate nuclei of the hypothalamus, and the CA1 region of the hippocampus. Sex differences for GABA occur only on postnatal days 1 and 5. However, sex differences in aspartate occur later in development (postnatal day 20). The CA1 region of males has a significantly greater concentration of GABA, glutamate and aspartate than females on postnatal day 1. In addition, treatment of females with testosterone propionate on the day of birth results in increased GABA levels, suggesting that these sex differences may be the result of hormone exposure during development. We hypothesize that these hormonally mediated sex differences in amino acid transmitters early in development contribute to the establishment of sexually dimorphic neuronal architecture in the adult.

Di Fiore, M. M., L. Assisi, et al. (1998). "D-aspartic acid is implicated in the control of testosterone production by the vertebrate gonad. Studies on the female green frog, Rana esculenta." J Endocrinol 157(2): 199-207.

In the present study we report the occurrence of D-aspartic acid (D-Asp) in the ovary of the green frog Rana esculenta and its putative involvement in testosterone production by the gonad. In the ovary, D-Asp concentrations undergo significant variations during the main phases of the sexual cycle. In spawning females (March), its concentration was low (2.5 +/- 1.1 nmol/g ovary) and during the post-reproductive period (June) it increased and reached its peak level (58.0 +/- 10.1 nmol/g) in October. In that month, vitellogenesis occurs in a new set of ovarian follicles and continues until the next spring. The concentrations of D-Asp in the ovary and of testosterone in the ovary and in the plasma were inversely correlated during the reproductive cycle: when endogenous D-Asp was low (March), testosterone was high (36.9 +/- 4.8 ng/g ovary; 23.1 +/- 2.76 ng/ml plasma) and, in contrast, when the D-Asp concentration was high (October), the testosterone concentration was low (0.86 +/- 0.21 ng/g ovary and 5.0 +/- 1.3 ng/ml plasma). In vivo experiments, consisting of injection of D-Asp (2.0 mumol/g body weight) into the dorsal lymphatic sac of adult female frogs, demonstrated that this amino acid accumulates significantly in the ovary. After 3 h, moreover, it caused a decrease in testosterone level in the plasma of about 80%. This inhibition was reversible: within 18 h after the amino acid injection, as the D-Asp concentration in the ovary decreased, the testosterone titre was restored in both ovary and plasma. In vitro experiments, conducted in isolated ovarian follicles, confirmed this phenomenon and identified these gonadal components as the putative D-Asp targets. Other amino acids (L-Asp, D-Glu, L-Glu, D-Ala and L-Ala) used instead of D-Asp were ineffective. These findings indicate that D-Asp is involved in the control of androgen secretion by the ovary in this amphibian species, revealing a more complex system for control of this androgen synthesis than was previously believed to exist.

Di Fiore, M. M., C. Lamanna, et al. (2008). "Opposing effects of D-aspartic acid and nitric oxide on tuning of testosterone production in mallard testis during the reproductive cycle." Reprod Biol Endocrinol 6: 28.

D-Aspartic acid (D-Asp) and nitric oxide (NO) play an important role in tuning testosterone production in the gonads of male vertebrates. In particular, D-Asp promotes either the synthesis or the release of testosterone, whereas NO inhibits it. In this study, we have investigated for the first time in birds the putative effects of D-Asp and NO on testicular testosterone production in relation to two phases of the reproductive cycle of the adult captive wild-strain mallard (Anas platyrhynchos) drake. It is a typical seasonal breeder and its cycle consists of a short reproductive period (RP) in the spring (April-May) and a non reproductive period (NRP) in the summer (July), a time when the gonads are quiescent. The presence and the localization of D-Asp and NO in the testis and the trends of D-Asp, NO and testosterone levels were assessed during the main phases of the bird's reproductive cycle. Furthermore, in vitro experiments revealed the direct effect of exogenously administered D-Asp and NO on testosterone steroidogenesis. METHODS: By using immunohistochemical (IHC) techniques, we studied the presence and the distributional pattern of D-Asp and NO in the testes of RP and NRP drakes. D-Asp levels were evaluated by an enzymatic method, whereas NO content, via nitrite, was assessed using biochemical measurements. Finally, immunoenzymatic techniques determined testicular testosterone levels. RESULTS: IHC analyses revealed the presence of D-Asp and NO in Leydig cells. The distributional pattern of both molecules was in some way correlated to the steroidogenic pathway, which is involved in autocrine testosterone production. Indeed, whereas NO was present only during the NRP, D-Asp was almost exclusively present during the RP. Consistently, the high testosterone testicular content occurring during RP was coupled to a high D-Asp level and a low NO content in the gonad. By contrast, in sexually inactive drakes (NRP), the low testosterone content in the gonad was coupled to a low D-Asp content and to a relatively high NO level. Consequently, to determine the exogenous effects of the two amino acids on testosterone synthesis, we carried out in vitro experiments using testis sections deriving from both the RP and NRP. When testis slices were incubated for 60 or 120 min with D-Asp, testosterone was enhanced, whereas in the presence of L-Arg, a precursor of NO, it was inhibited. CONCLUSION: Our results provide new insights into the involvement of D-Asp and NO in testicular testosterone production in the adult captive wild-strain mallard drake. The localization of these two molecules in the Leydig cells in different periods of the reproductive cycle demonstrates that they play a potential role in regulating local testosterone production.

Ebling, F. J., A. Mirakhur, et al. (1994). "Photoperiodically induced changes in glutamatergic stimulation of LH secretion in male Syrian hamsters: role of circulating testosterone and endogenous opioids." Gen Comp Endocrinol 96(1): 50-62.

In seasonally breeding mammals, the sensitivity of LH secretion to stimulation by the glutamate agonist N-methyl-D-aspartic acid (NMDA) is lower in the sexually active condition than in animals with testicular regression. One experiment determined if this increased sensitivity to NMDA in the reproductively inactive animal reflects reduced circulating testosterone. Responses to NMDA were determined during long days (LD) and short days (SD) in castrated hamsters bearing silastic testosterone implants, designed to maintain constant serum testosterone concentrations throughout a photoperiodically induced seasonal cycle. As expected, no significant effect of NMDA (50 mg/kg BW, sc) on secretion of LH occurred in testosterone-implanted castrate or intact control hamsters when challenged in LD. In contrast, both groups of hamsters responded to this dose of NMDA after 8 weeks exposure to SD, despite the maintenance of high serum testosterone concentrations in the castrate group. Moreover, the increased response to NMDA was not a reflection of lower LH concentrations associated with this photoperiod, because a response to NMDA persisted after removal of implants when endogenous secretion of LH had increased. Thus, the low circulating concentrations of testosterone in male hamsters exposed to an inhibitory SD photoperiod cannot explain the increased response to glutamatergic stimulation in the sexually inactive state. Photoperiod, acting centrally, is the major determinant of the response to activation of NMDA receptors. Other experiments investigated whether the lack of response to glutamatergic stimulation in the LD sexually active state results from endogenous opioid (EOP) tone that inhibits further increases in LH secretion at this stage of the reproductive cycle. If this is so, then pretreatment with an opioid antagonist would reveal or increase the stimulatory effect of NMDA on secretion of LH. Hamsters in LD were pretreated with the opioid antagonist naloxone (NAL; 5 mg/kg BW sc) before NMDA treatment (50 mg/kg BW sc), and blood samples collected 15 min later. Compared with controls, serum LH was significantly elevated in hamsters pretreated with NAL, but NMDA alone did not elevate LH. Surprisingly, LH concentrations in hamsters pretreated with NAL and then injected with NMDA were significantly lower than in hamsters receiving NAL only. Treatment with a submaximal dose of NAL (0.1 mg/kg) did not increase serum LH, nor did it reveal a stimulatory effect of subsequent NMDA treatment. The results demonstrate that the decrea

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